Benzenesulfonamide derivative and process for preparing thereof

ABSTRACT

A benzenesulfonamide derivative of the formula  I!: ##STR1## wherein Ring A and Ring B are the same or different and each substituted or unsubstituted benzene ring, Q is a single bond or a group of the formula: --O--, --S--, --SO--, --SO 2  -- or --CH 2  --, Y is a group of the formula: --O--, --S-- or --NH--, Alk is lower alkylene group or lower alkenylene group, Z is a single bond or a group of the formula: --O-- or --NH--, R is a substituted or unsubstituted aromatic heterocyclic or aryl group, R 1  is hydrogen atom, trifluoromethyl group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted lower alkenyl group, mono- or di-lower alkylamino group, substituted or unsubstituted lower alkylthio group, substituted or unsubstituted lower alkoxy group, substituted or unsubstituted lower alkynyl group, aromatic heterocyclic group, substituted or unsubstituted aliphatic heterocyclic group or aryl group, provided that when Z is a single bond, R is a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof, and processes for preparing the same, these compounds having endothelin antagonistic activity and being useful in the prophylaxis or treatment of various diseases caused by endothelin.

This is a continuation of application Ser. No. 08/356,958 filed Dec. 16,1994, now U.S. Pat. No. 5,589,478.

FIELD OF THE INVENTION

The present invention relates to a novel benzenesulfonamide derivativehaving endothelin antagonistic activity, and a process for preparing thesame.

PRIOR ART

Endothelin is a polypeptide consisting of 21 amino acids which is firstisolated from the culture supernatant of porcine aortic endothelialcells. Now, it is known to be a potent vasoconstrictor,bronchoconstrictor and mitogen. It has also been reported that the levelof endothelin is significantly increased in the blood of patients withessential hypertension, acute myocardial infarction, pulmonaryhypertension, Raynaud disease, diabetes, atherosclerosis, and in theblood and the washing of airway of patients with asthma, compared withthat of the normal human being. Thus, endothelin is an endogenousbioactive substance which stimulates durably and directly or indirectlythe vascular or non-vascular smooth muscle. The excess production orexcess secretion of endothelin seems to be one of the causes forhypertension, pulmonary hypertension, renal hypertension, Raynauddisease, bronchial asthma, gastric ulcer, inflammatory bowl disease(Crohn's disease), shock, carcinogenesis, restenosis after angioplasty,organ dysfunction after transplantation, diabetes, thrombosis,arteriosclerosis, heart failure, acute renal insufficiency,glomerulonephritis, cyclosporin-induced nephrotoxicity, myocardialinfarction, angina pectoris, arrhythmia, glaucoma, migraine,cerebrovascular spasm and cerebral infarction. Thus, a compound whichstrongly antagonizes endothelin has been considered to be useful in thetreatment of the above various diseases.

On the other hand, Japanese Patent First Publication (Kokai) Nos.155864/1993 and 222003/1993 disclose as a benzenesulfonamide derivativehaving endothelin antagonistic activity N-{ 5-substituted phenyl (orsubstituted phenoxy)!-6-hydroxyalkoxypyrimidin-4-yl}-substitutedbenzenesulfonamides, and the like.

BRIEF DESCRIPTION OF THE INVENTION

An object of the present invention is to provide a novelbenzenesulfonamide derivative having an excellent endothelinantagonistic activity. Another object of the present invention is toprovide processes for preparing the same.

DETAILED DESCRIPTION OF INVENTION

The present invention relates to a benzenesulfonamide derivative of theformula I!: ##STR2## wherein Ring A and Ring B are the same or differentand each a substituted or unsubstituted benzene ring,

Q is a single bond or a group of the formula: --O--, --S--, --SO--,--SO₂ -- or --CH₂ --,

Y is a group of the formula: --O--, --S-- or --NH--,

Alk is a lower alkylene group or a lower alkenylene group,

Z is a single bond or a group of the formula: --O-- or --NH--,

R is a substituted or unsubstituted aromatic heterocyclic or aryl group,

R¹ is hydrogen atom, trifluoromethyl group, a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted loweralkenyl group, a mono- or di-lower alkylamino group, a substituted orunsubstituted lower alkylthio group, a substituted or unsubstitutedlower alkoxy group, a substituted or unsubstituted lower alkynyl group,an aromatic heterocyclic group, a substituted or unsubstituted aliphaticheterocyclic group or an aryl group, provided that when Z is a singlebond, R is a substituted or unsubstituted aromatic heterocyclic group,

or a pharmaceutically acceptable salt thereof.

In the present compounds I!, the substituent of Ring A or Ring Bincludes, for example, a halogen atom; a lower alkyl group; a loweralkoxy group; a lower alkenyl group; a lower alkynyl group; a cycloalkylgroup; a lower alkylthio group; trifluoromethyl group; carboxyl group;cyano group; tetrazolyl group; formyl group; carbamoyl group; a mono- ordi-lower alkylaminocarbonyl group; a lower alkoxycarbonyl group; a loweralkoxycarbonyl-lower alkoxy group; a lower alkoxycarbonyl-lower alkylgroup; a lower alkoxycarbonyl-lower alkenyl group; a di-loweralkoxy-substituted lower alkyl group; a hydroxy-substituted lower alkylgroup; a carboxyl-substituted lower alkyl group; a carboxyl-substitutedlower alkenyl group; a carboxy-substituted lower alkoxy group; abromopyrimidinyloxy-lower alkyl group; a lower alkylenedioxy group; anaryl-lower alkoxy group; or an arylaminocarbonyl group, and the like.

The substituent of the lower alkyl group includes, for example, ahalogen atom, carboxyl group, a lower alkoxycarbonyl group, an aromaticheterocyclic group or an aryl group, and the like. The substituent ofthe lower alkoxy group includes, for example, hydroxy group, ahydroxy-lower alkoxy group, and the like. The substituent of the loweralkynyl group includes, for example, carboxyl group, and the like. Thesubstituent of the aliphatic heterocyclic group includes, for example, alower alkyl group, and the like.

The substituent of the aromatic heterocyclic or aryl group includes, forexample, a halogen atom; a protected or unprotected hydroxy group; nitrogroup; cyano group; amino group; formyl group; carboxyl group; carbamoylgroup; an N-lower alkylcarbamoyloxy group; an N-hydroxyiminomethylgroup; an N-lower alkoxyiminomethyl group; a lower alkyl group; ahydroxy-substituted lower alkyl group; a cycloalkyl group; a loweralkoxy-lower alkyl group; a lower alkoxycarbonyl-lower alkenyl group;trifluoromethyl group; a hydroxy- and aryl-substituted lower alkylgroup; a lower alkylthio group; a mono- or di-lower alkylamino group; alower alkanoylamino group; a lower alkoxy group; a lower alkoxy groupsubstituted by a protected or unprotected carboxyl group; an aryloxygroup; a lower alkoxycarbonyl group; a lower alkoxy-lower alkenyl group;a lower alkanoyl group; an arylcarbonyl group; a lower alkenyloxy group;a hydroxy-substituted lower alkynyl group; a lower alkynyl group beingoptionally protected by a trimethylsilyl group; a cyano-lower alkoxygroup; a cycloalkyl-lower alkoxy group; a lower alkylsulfinyl group; alower alkylsulfonyl group; an aryl group; a phenyl-lower alkyl group; anaromatic heterocyclic-substituted lower alkyl group; an aromaticheterocyclic-substituted lower alkoxy group; a phenyl-lower alkenylgroup; a phenyl-lower alkoxy group; an arylcarbonylamino group; anaromatic heterocyclic-substituted oxy group having optionally 1 to 3substituents selected from a halogen atom and a lower alkyl group; or anaromatic heterocyclic group having optionally a lower alkyl substiuent,and the like.

Ring A and/or Ring B may have the same or different 1 to 3 substituentsof the above mentioned substituents. The lower alkyl group, the aromaticheterocyclic group and/or the aryl group may have the same or different1 to 4 substituents of the above mentioned substituents, respectively.

The protecting group for hydroxy group and/or carboxyl group may be anyconventional one which can be a protecting group for hydroxy groupand/or carboxyl group, respectively, and the protecting group forhydroxy group includes, for example, benzyl group, methoxymethyl group,tetrahydropyranyl group, and the like, and the protecting group forcarboxyl group includes, for example, methyl group, ethyl group,tert-butyl group, benzyl group, and the like.

The aromatic heterocyclic group is preferably an aromaticheteromonocyclic or heterobicyclic group having 1 to 4 heteroatomsselected from nitrogen atom, oxygen atom and sulfur atom, for example,pyrrolyl group, imidazolyl group, furyl group, thienyl group, thiazolylgroup, isooxazolyl group, oxazolyl group, oxazolinyl group, pyrazolylgroup, quinazolinyl group, thienopyrimidinyl group, pyridyl group,pyrimidinyl group, pyridazinyl group, pyrazinyl group, triazinyl group,tetrazolyl group, quinolyl group, isoquinolyl group, quinoxalinyl group,benzothiazolyl group, benzoxazolyl group, benzimidazolyl group, and thelike.

The aryl group and the aryl moiety in the arylcarbonylamino group, thearylaminocarbonyl group, the aryloxy group and the arylcarbonyl groupare, for example, phenyl group, a lower alkoxyphenyl group or naphthylgroup.

The aliphatic heterocyclic group is preferably an aliphaticheteromonocyclic or heterobicyclic group having 1 to 4 heteroatomsselected from nitrogen atom, oxygen atom and sulfur atom, for example,piperazinyl group, pyrrolidinyl group, piperidyl group, homopiperidylgroup, thiomorpholinyl group, morpholinyl group, and the like.

Among the desired compounds I! of the present invention, thepharmaceutically preferable compounds are compounds of the formula I!wherein Ring A is a benzene ring substituted by a lower alkyl group; oneor two lower alkoxy groups; a lower alkoxycarbonyl-lower alkyl group; ahydroxy-substituted lower alkyl group; or a lower alkoxycarbonyl-loweralkoxy group, Ring B is a benzene ring substituted by formyl group;trifluoromethyl group; a lower alkyl group; one or two lower alkoxygroups; a lower alkylenedioxy group; a hydroxy-lower alkyl group; or alower alkoxycarbonyl group, Q is a single bond or a group of theformula: --O-- or --S--, Y is a group of the formula: --O--, Alk is alower alkylene group, Z is a group of the formula: --O--, R is a phenylgroup having optionally a substituent selected from amino group, nitrogroup, a halogen atom and a hydroxy-lower alkyl group; a pyridyl grouphaving optionally a substituent selected from amino group, nitro group,trifluoromethyl group and a lower alkanoylamino group; a pyrimidinylgroup having optinally a substituent selected from a halogen atom,formyl group, thienyl group, furyl group, pyridyl group, a lower alkylgroup, a lower alkylthio group, a lower alkanoyl group, a lower alkynylgroup, a lower alkenyloxy group, a lower alkoxy group, a loweralkylsulfinyl group, a lower alkylsulfonyl group, a cyano-substitutedlower alkoxy group, thiazolyl group, a lower alkyl-substituted thienylgroup, a lower alkyl-substituted pyrrolyl group, a phenyl group and alower alkoxyphenyl group; or a benzothiazolyl group, and R¹ is hydrogenatom, a lower alkyl group, pyridyl group, morpholinyl group orpyrimidinyl group.

The pharmaceutically more preferable compounds are compounds of theformula I! wherein Ring A is a benzene ring substituted by a lower alkylgroup, Ring B is a benzene ring substituted by a halogen atom, a loweralkyl group or a lower alkoxy group, R is a pyrimidinyl groupsubstituted by a halogen atom, thienyl group, furyl group or a loweralkylthio group, and R¹ is hydrogen atom or pyrimidinyl group.

Among the desired compounds I! of the present invention, otherpreferable compounds are compounds of the formula I! wherein Ring A is abenzene ring substituted by a lower alkyl group, Ring B is a benzenering substituted by a lower alkyl group or a lower alkoxy group, Q is asingle bond or a group of the formula: --O--, Y is a group of theformula: --O--, Alk is a lower alkylene group, Z is a group of theformula: --O--, R is a pyrimidinyl group having optionally a substituentselected from a halogen atom, formyl group, cyano group, hydoxy group, alower alkoxy group, a lower alkylthio group, a lower alkanoyl group, alower alkenyloxy group, a lowr alkynyl group, a lower alkylsulfonylgroup, a lower alkylsufinyl group, a lowr alkylamino-lower alkanoyloxygroup, a cyano-lower alkoxy group, a hydroxy-lower alkyl group, a loweralkoxy-lower alkenyl group, a lower alkyl-pyrrolyl group, thiazolylgroup, thienyl group, a lower alkyl-thienyl group, furyl group, pyridylgroup, a di-lower alkyl-oxazolinyl group and phenyl group, and R¹ ishydrogen atom, pyridyl group, pyrimidinyl group or morpholinyl group.

The more preferable compounds are compounds of the formula I! wherein Ris a pyrimidinyl group having a substituent selected from a halogenatom, a lower alkylthio group, a lower alkoxy group, a lower alkanoylgroup, a hydroxy-lower alkyl group, a lower alkoxy-lower alkenyl group,thienyl group, furyl group, pyridyl group and phenyl group, and R¹ ishydrogen atom, pyrimidinyl group or morpholinyl group.

The desired compounds I! of the present invention may exist in the formof an optical isomer based on an asymmetric carbon atom thereof, and thepresent invention also includes these optical isomers and a mixturethereof.

The desired compounds I! of the present invention may be clinically usedeither in the form of a free form or in the form of a pharmaceuticallyacceptable salt thereof. The pharmaceutically acceptable salt includesan acid-addition salt with an inorganic acid or organic acid, salts withan inorganic base, organic base or amino acid, for example,hydrochloride, sulfate, hydrobromide, methanesulfonate, acetate,fumarate, maleate, oxalate, an alkali metal salt (e.g. sodium,potassium, etc.), an alkaline earth metal salt (e.g. magnesium, calcium,etc.), triethylamine salt, a salt with lysine, and the like.

The desired compounds I! of the present invention or a pharmaceuticallyacceptable salt thereof may be administered either orally orparenterally in the form of a conventional pharmaceutical preparationsuch as tablets, granules, capsules, powders, injections, inhalants, andthe like.

The dosage of the desired compounds I! of the present invention and apharmaceutically acceptable salt thereof may vary according to theadministration route, ages, weights and conditions of the patients, butit is usually in the range of about 0.01 to 100 mg/kg/a day.

According to the present invention, the desired compounds I! may beprepared by the following Process A, B, C or D.

Process A

The desired compounds I! of the present invention may be prepared byreacting a compound of the formula II!: ##STR3## wherein X¹ is areactive residue, and the other symbols are the same as defined above,with a compound of the formula III!:

    H--Y--Alk--Z--R                                             III!

wherein the symbols are the same as defined above, or a salt thereof.

Process B

The compounds I! may also be prepared by reacting a compound of theformula IV!: ##STR4## wherein the symbols are the same as defined above,or a salt thereof, with a compound of the formula V!: ##STR5## whereinX² is a reactive residue, and Ring A is the same as defined above.

Process C

Among the desired compounds I! of the present invention, the compound ofthe formula I! wherein Z is a group of the formula: --O-- or --NH--,i.e. the compound of the formula I-a!: ##STR6## wherein Z¹ is a group ofthe formula: --O-- or --NH--, and the other symbols are the same asdefined above, may be prepared by reacting a compound of the formulaVI!: ##STR7## wherein the symbols are the same as defined above, or asalt thereof, with a compound of the formula VII!:

    X.sup.3 --R                                                 VII!

wherein X³ is a reactive residue, and the other symbols are the same asdefined above.

Process D

Moreover, among the desired compounds I! of the present invention, thecompound of the formula I! wherein Q is a single bond, i.e. the compoundof the formula I-b!: ##STR8## wherein the symbols are the same asdefined above, may be prepared by reacting a compound of the formulaVIII!: ##STR9## wherein X⁴ is a reactive residue, and the other symbolsare the same as defined above, or a salt thereof, with a compound of theformula IX!: ##STR10## wherein W is a lower alkyl group, and Ring B isthe same as defined above.

The salts of the compounds III!, IV!, VI! and VIII! are, for example,salts with an inorganic acid (e.g. hydrochloride, sulfate, etc.), andsalts with an inorganic base (e.g. an alkali metal salt, an alkalineearth metal salt, etc.).

The reactive residues for X¹, X², X³ and X⁴ are preferably a halogenatom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group, but ahalogen atom is more preferable.

The above Processes are preferably carried out as follows.

Process A

The reaction of the compound II! and the compound III! or a salt thereofis carried out in the presence of an acid acceptor in a suitable solventor without a solvent. The acid acceptor is preferably an alkali metalhydride, an alkali metal carbonate, an alkali metal amide, an alkalimetal alkoxide, an alkyl-alkali metal, an alkali metal, an alkalineearth metal, an alkali metal hydroxide, an alkaline earth metalhydroxide, an organic base (e.g. 1,8-diazabicyclo 5.4.0!undeca-7-ene,etc.), and the like. The solvent includes, for example,dimethylsulfoxide, dimethylacetamide, dimethylformamide,hexamethylphosphoramide, sulfolane, 1,3-dimethyl-2-imidazolidinone,dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, andthe like. The reaction is preferably carried out at a temperature fromroom temperature to 150° C., preferably at a temperature from roomtemperature to 100° C.

Process B

The reaction of the compound IV! or a salt and the compound V! iacarried out in the presence of an acid acceptor in a suitable solvent orwithout a solvent. The acid acceptor and the solvent may be the sameacid acceptors or the solvents for the above Process A. The reaction ispreferably carried out at a temperature from 0° C. to 150° C., morepreferably at a temperature from room temperature to 100° C. Thereaction may preferably proceed in the presence of a catalytic amount ofa phase transfer catalyst such as tetrabutylammonium hydrogen sulfate,trimethylbenzylammonium chloride, 18-crown-6, etc.

Process C

The reaction of the compound VI! or a salt thereof and the compoundVIII! is carried out in the presence of an acid acceptor in a suitablesolvent or without a solvent. The acid acceptor may be the same acidacceptor for the above mentioned Process A. The solvent includes, forexample, dimethylsulfoxide, dimethylacetamide, dimethylformamide,1,3-dimethyl-2-imidazolidinone, ethylene glycol dimethyl ether,hexamethylphosphoramide, sulfolane, dioxane, tetrahydrofuran, toluene,and the like. The reaction is preferably carried out at a temperaturefrom room temperature to 150° C., more preferably at a temperature fromroom temperature to 100° C.

Process D.

The reaction of the compound VIII! or a salt thereof and the compoundIX! is carried out in the presence of a catalyst in a suitable solvent.The catalyst includes, for example, a palladium catalyst such asbis(triphenylphosphine)palladium (II) chloride, palladium (II) acetate,tetrakis(triphenylphosphine)palladium (O), and the like. The reactionmay preferably proceed in the presence of a copper (I) salt such ascopper (I) chloride, copper (I) bromide, copper (I) iodide, etc.,according to the method disclosed in Journal of Organic Chemistry Vol.58, p. 1963 (1993). The solvent includes, for example, dioxane, ethyleneglycol dimethyl ether, dimethylacetamide, dimethyformamide,hexamethylphosphoramide, benzene, tetrahydrofuran, toluene, ethylacetate, a lower alcohol, methylene chloride, chloroform, carbontetrachloride, 1,3-dimethyl-2-imidazolidinone, acetic acid, diethylether, dimethoxyethane, water, or a mixture thereof. The reaction ispreferably carried out at a temperature from 50° C. to 100° C.

The desired compounds I! of the present invention can be converted eachother to the other desired compound I!. Such conversion of the presentcompounds I! into the other compound I! may be carried out according tothe kinds of the substituents thereof, but is carried out according tothe following Step (a) to (w).

Step (a):

The desired compound I! wherein R is a substituted aromatic heterocyclicor aryl group can be prepared by reacting the compound I! wherein thecorresponding R is a halogen-substituted aromatic heterocyclic or arylgroup with a trialkyl-tin compound with the group to substitute in thepresence of a catalyst. The catalyst may be any ones which are used inthe above mentioned Process D. The reaction is preferably carried out ata temperature from room temperature to 100° C.

Step (b):

The desired compound I! wherein R is a lower alkanoyl group (e.g. acetylgroup, etc.)-substituted aromatic heterocyclic or aryl group can beprepared by acid-treatment of the compound I! wherein the correspondingR is a lower alkoxy-lower alkenyl group (e.g. 1-ethoxyvinyl group,etc.)-substituted aromatic heterocyclic or aryl group. The acidincludes, for example, hydrochloric acid, sulfuric acid,p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid,acetic acid, etc. The reaction is preferably carried out at atemperature from 0° C. to room temperature.

Step (c):

The desired compound I! wherein R is a hydroxy-substituted lower alkylgroup-substituted aromatic heterocyclic or aryl group can be prepared bytreating the compound I! wherein the corresponding R is a loweralkanoyl- or formyl-substituted aromatic heterocyclic or aryl group witha reducing agent. The reducing agent includes, for example, sodiumborohydride, lithium borohydride, lithium aluminum hydride, di-isobutylaluminum hydride, etc. The reaction is preferably carried out at atemperature from 0° C. to room temperature.

Step (d):

The desired compound I! wherein R is a lower alkyl group-substitutedaromatic heterocyclic or aryl group can be prepared by subjecting thecompound I! wherein the corresponding R is a hydroxy-substituted loweralkyl-substituted aromatic heterocyclic or aryl group to halogenation,followed by reduction of the product. The halogenation reaction iscarried out by reacting the compound I! with a halogenating agent suchas thionyl chloride, phosphorus oxychloride, phosphorus pentachloride,phosphorus tribromide, etc. The reduction is carried out by treatingwith a palladium catalyst such as palladium-carbon, palladium-bariumsulfate, palladium-aluminum oxide, palladium-black, etc., preferably inthe presence of an acid acceptor under hydrogen atmosphere. The acidacceptor is preferably triethylamine, pyridine, potassium carbonate,sodium hydrogen carbonate, sodium acetate, etc. The reaction ispreferably carried out at a temperature from room temperature to 60° C.

Step (e):

The desired compound I! wherein R is an unsubstituted aromaticheterocyclic or aryl group can be prepared by reduction of the compoundI! wherein the corresponding R is a halogen-substituted aromaticheterocyclic or aryl group. The reduction is preferably carried outunder the same conditions as those of the reduction of the above Step(d).

Step (f):

The desired compound I! wherein R is an unsubstituted aromaticheterocyclic or aryl group can be prepared by subjecting the compound I!wherein the corresponding R is a lower alkylthio-substituted aromaticheterocyclic or aryl group to desulfurization. The desulfurizationreaction is preferably carried out in the presence of a catalyst such asRaney nickel, palladium-carbon, etc., at a temperature from roomtemperature to 50° C.

Step (g):

The desired compound I! wherein R is an aromatic heterocyclic or arylgroup substituted by a formyl group, a hydroxy-substituted lower alkylgroup, or a hydroxy- and aryl-substituted lower alkyl group can beprepared by subjecting the compound I! wherein the corresponding R is ahalogen-substituted aromatic heterocyclic or aryl group to lithiation,followed by reacting the product with a corresponding carbonyl compound(e.g. dimethylformamide, acetone, benzaldehyde, etc.). The lithiation ispreferably carried out by using a lithiating agent such as n-butyllithium, s-butyl lithium, t-butyl lithium, etc. The reaction is carriedout at a temperature from -100° C. to 25° C.

Step (h):

The desired compound I! wherein R is an amino-substituted aromaticheterocyclic or aryl group can be prepared by reduction of the compoundI! wherein the corresponding R is a nitro-substituted aromaticheterocyclic or aryl group. The reduction is carried out in the presenceof a transition metal catalyst under hydrogen atmosphere, or by reactingwith a reducing agent. The transition metal catalyst includes, forexample, palladium-carbon, palladium-aluminum oxide, palladium-black,colloidal palladium, platinum oxide, Raney nickel, etc., and thereducing agent includes, for example, lithium aluminum hydride, tin,stannous chloride, zinc, iron, etc. The reaction is preferably carriedout at a temperature from -20° C. to 80° C.

Step (i):

The desired compound I! wherein R is a lower alkanoylamino-substitutedor arylcarbonylamino-substituted aromatic heterocyclic or aryl group canbe prepared by acylating the compound I! wherein the corresponding R isan amino-substituted aromatic heterocyclic or aryl group. The acylatingagent includes, for example, a carboxylic acid or a reactive derivativethereof (e.g. an acid chloride, an acid bromide, an acid anhydride, amixed acid anhydride, etc.). When a free carboxylic acid is used, thereaction is preferably carried out in the presence of a condensing agentsuch as N,N'-dicyclohexylcarbodiimide,N-dimethylaminopropyI-N'-ethylcarbodiimide, diethylphosphoric cyanide,diphenylphosphoric azide, etc. When a reactive derivative of carboxylicacid is used, the reaction is preferably carried out in the presence ofan acid acceptor such as an alkali metal hydroxide, an alkali metalhydrogen carbonate, an alkali metal carbonate, an organic base (e.g.triethylamine, pyridine, etc.), and the like. The reaction is preferablycarried out at a temperature from -20° C. to 100° C.

Step (j):

The desired compound I! wherein R is a mono- or di-loweralkylamino-substituted aromatic heterocyclic or aryl group can beprepared by subjecting the compound I! wherein the corresponding R is anamino-substituted aromatic heterocyclic or aryl group to alkylation. Thealkylation is carried out by (i) reacting in the presence of an acidacceptor with a lower alkyl halide (e.g. a lower alkyl chloride, a loweralkyl bromide, etc.) or a lower alkyl sulfonate (e.g. methanesulfonate,toluenesulfonate, etc.), and the like, or by (ii) subjecting a reactionproduct with a lower alkyl aldehyde to reduction in the presence of areducing agent. The acid acceptor includes, for example, an alkali metalhydroxide, an alkali metal hydrogen carbonate, an alkali metalcarbonate, an organic base (e.g. triethylamine, pyridine, etc.), and thelike. The reducing agent includes, for example, sodium borohydride,sodium triacetoxyborohydride, formic acid, etc. The reaction ispreferably carried out at a temperature from 0° C. to 100° C.

Step (k):

The desired compound I! wherein R is a tetrazolyl-substituted aromaticheterocyclic or aryl group can be prepared by reacting the compound I!wherein the corresponding R is a cyano-substituted aromatic heterocyclicor aryl group with tributyltin azide. The reaction is preferably carriedout at a temperature from 50° C. to 120° C.

Step (l):

The desired compound I! wherein R is a protected or unprotectedcarboxyl-substituted lower alkoxy-substituted aromatic heterocyclic oraryl group can be prepared by reacting the compound I! wherein thecorresponding R is a hydroxy-substituted aromatic heterocyclic or arylgroup with a protected or unprotected carboxyl-substituted lower alkylhalide or a protected or unprotected carboxyl-substituted lower alkylsulfonate, etc. The reaction is preferably carried out in the presenceof an acid acceptor such as an alkali metal hydroxide, an alkali metalhydrogen carbonate, an alkali metal carbonate, an organic base (e.g.triethylamine, pyridine, etc.). The reaction is preferably carried outat a temperature from 0° C. to 100° C. The protecting group for carboxylgroup may be any conventional protecting groups for carboxyl group, andthe protecting group can be removed by a conventional method which isselected according to the kind of the protecting group to be removed.

Step (m):

The desired compound I! wherein R is a lower alkoxy-loweralkyl-substituted aromatic heterocyclic or aryl group can be prepared byhalogenating the compound I! wherein the corresponding R is ahydroxy-substituted lower alkyl-substituted aromatic heterocyclic oraryl group, followed by alkoxylating the product. The halogenating agentmay be any halogenating agents used for Step (d). The reaction ispreferably carried out at a temperature from -20° C. to 100° C. Thealkoxylation reaction is carried out by reacting the product with alower alcohol such as methanol, ethanol, isopropanol, etc. Thealkoxylation reaction is preferably carried out in the presence of anacid acceptor, and the acid acceptor includes, for example, an alkalimetal hydroxide, an alkali metal hydrogen carbonate, an alkali metalcarbonate, an organic base (e.g. triethylamine, pyridine, etc.). Thereaction is preferably carried out at a temperature from -20° C. to 100°C.

Step (n):

The desired compound I! wherein R is a lower alkylsufinyl group- and/ora lower alkyl sulfonyl group-substituted aromatic heterocyclic or arylgroup can be prepared by reacting the compound I! wherein thecorresponding R is a lower alkylthio-substituted aromatic heterocyclicor aryl group in the presence of an oxidizing agent. The oxydizing agentis preferably 3-chloroperbenzoic acid, peracetic acid, hydrogenperoxide, pertrifluoroacetic acid, sodium periodate, sodim hypochlorite,potassium permanganate, and the like. The reaction is carried out at atemperature from 0° C. to 50° C.

Step (o):

The desired compound I! wherein R is a lower alkylthio-substitutedaromatic heterocyclic or aryl group can be prepared by reacting thecompound I! wherein the corresponding R is a loweralkylsufinyl-substituted aromatic heterocyclic or aryl group in thepresence of an acid anhydride, subjecting the product to hydrolysis togive a thiol compound, followed by reacting the thiol compound with alower alkyl halide in the presence of a base. The acid anhydride ispreferably trifluoroacetic anhydride, acetic anhydride, and the like.The base is preferably potassium carbonate, sodium carbonate, a loweralkoxy sodium (e.g. sodium methoxide, sodium ethoxide, etc.), and thelike. The reaction is preferably carried out at a temperature from 0° C.to 50° C.

Step (p):

The desired compound I! wherein R is a cyano-substituted aromaticheterocyclic or aryl group can be prepared by reacting the compound I!wherein the corresponding R is a halogen-substituted aromaticheterocyclic or aryl group with zinc cyanide in the presence of acatalyst. The catalyst is preferably the same catalysts for the aboveProcess D. The reaction is preferably carried out at a temperature from60° C. to 100° C.

Step (q):

The desired compound I! wherein R is a trimethylsilyl-substituted loweralkynyl- or a hydroxy-substituted lower alkynyl-substituted aromaticheterocyclic or aryl group can be prepared by subjecting the compound I!wherein the corresponding R is a halogen-substituted aromaticheterocyclic or aryl group to trimethylsilyl-substituted loweralkynylation, or to hydroxy-substituted lower alkynylation. Thetrimethylsilyl-substituted lower alkynylation, or thehydroxy-substituted lower alkynylation is carried out in the presence ofa catalyst and an organic base. The catalyst is preferably the samecatalysts for the above Process D, and the organic base is preferablythe same organic bases for the above Step (i). The reaction canpreferably proceed in the presence of a copper (I) salt like the aboveProcess D. The reactions is carried out at a temperature from roomtemperature to 100° C.

Step (r):

The desired compound I! wherein R is a lower alkynyl-substitutedaromatic heterocyclic or aryl group can be prepared by reacting thecompound I! wherein the corresponding R is a trimethylsilyl-substitutedlower alkynyl-substituted aromatic heterocyclic or aryl group in thepresence of an acid or an inorganic base. The acid includes, forexample, hydrochloric acid, sulfuric acid, hydrobromic acid, etc., andthe base includes, for example, potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, etc. The reaction is preferablycarried out at a temperature from 0° C. to room temperature.

Step (s):

The desired compound I! wherein R is a phenyl-lower alkyl-substitutedaromatic heterocyclic or aryl group can be prepared by reacting thecompound I! wherein the corresponding R is a phenylalkenyl-substitutedaromatic heterocyclic or aryl group in the presence of a catalyst. Thecatalyst may be the same catalysts used for the above Step (d). Thereaction is preferably carried out at a temperature from roomtemperature to 60° C.

Step (t):

The desired compound I! wherein Ring A and/or Ring B are a benzene ringsubstituted by formyl group can be prepared by reacting the compound I!wherein the corresponding Ring A and/or Ring B are a benzene ringsubstituted by a di-lower alkoxy-substituted lower alkyl group in thepresence of an acid. The acid includes, for example, an organic acidsuch as p-toluenesulfonic acid, oxalic acid, etc., and an inorganic acidsuch as hydrochloric acid, sulfuric acid, hydrobromic acid, etc. Thereaction is preferably carried out at a temperature from 0° C. to 50° C.

Step (u):

The desired compound I! wherein Ring A and/or Ring B are a benzene ringsubstituted by a lower alkoxycarbonyl-lower alkenyl group can beprepared by reacting the compound I! wherein the corresponding Ring Aand/or Ring B are a benzene ring substituted by formyl group with atriphenylphosphorane with a group to substitute. The reaction ispreferably carried out at a temperature from room temperature for 60° C.

Step (v):

The desired compound I! wherein Ring A and/or Ring B are a benzene ringsubstituted by a carboxy-substituted lower alkenyl group can be preparedby reacting the compound I! wherein the corresponding Ring A and/or RingB are a benzene ring substituted by a lower alkoxycarbonyl-lower alkenylgroup in the presence of an inorganic base. The inorganic base includes,for example, sodium hydroxide, etc. The reaction is carried out at atemperature from 0° C. to room temperature.

Step (w):

The desired compound I! wherein Q is a group of the formula: --SO-- or--SO₂ -- can be prepared by reacting the compound I! wherein thecorresponding Q is a group of the formula: --S-- in the presence of anoxidizing agent. The oxidizing agent includes, for example,3-chloroperbenzoic acid, peracetic acid, hydrogen peroxide,pertrifluoroacetic acid, sodium periodate, soiudm hypochorite, potassiumpermanganate, and the like. The reaction is preferably carried out at atemperature from 0° C. to 50° C.

The solvent used for the reactions of Steps (a) to (w) may be any onewhich does not affect the reaction, for example, dioxane, ethyleneglycol dimethyl ether, dimethylacetamide, dimethylformamide,hexamethylphosphoramide, benzene, tetrahydrofuran, toluene, ethylacetate, a lower alcohol, methylene chloride, chloroform, carbontetrachloride, 1,3-dimethyl-2-imidazolidinone, acetic acid, diethylether, dimethoxyethane, dimethylsulfoxide, water, or a mixture thereof.

The starting compounds II! and VI! of the present invention may beprepared according to a method disclosed in Japanese Patent FirstPublication (Kokai) No. 155864/1993 or Japanese Patent First Publication(Kokai) No. 222003/1993. That is, the compound II! wherein Q is a singlebond may be prepared by treating a compound of the formula X!: ##STR11##wherein Ring B is the same as defined above, with a halogenating agent(e.g. thionyl chloride, etc.), treating the resulting corresponding acidhalide compound with an alcohol, followed by reacting the resultingester compound with diethyl carbonate in the presence of a base (e.g.sodium hydride, potassium t-butoxide, etc.) to give a compound of theformula XI!: ##STR12## wherein Ring B is the same as defined above.Further, the compound XI! is treated with ammonia to give an amidecompound of the formula: ##STR13## wherein Ring B is the same as definedabove, followed by reacting the resulting compound with a compound ofthe formula:

    R.sup.1 --COOC.sub.2 H.sub.5

wherein R¹ is the same as defined above, in the presence of a base (e.g.sodium ethylate, etc.) to give a compound of the formula XII!: ##STR14##wherein the symbols are the same as defined above, or the compound XI!is reacted with an amidine compound of the formula XIII!: ##STR15##wherein R¹ is the same as defined above, in the presence of a base (e.g.sodium methoxide, etc.) to give the compound XII!. Further, the hydroxygroups of the compound XII! are converted into a reactive residue bytreating with a halogenating agent (e.g. phosphorus oxychloride, etc.)to give a compound of the formula XIV!: ##STR16## wherein R⁵ is areactive residue and the other symbols are the same as defined above,followed by reacting the resulting compound XIV! with a compound of theformula XV!: ##STR17## wherein Ring A is the same as defined above, inthe presence of an acid acceptor (e.g. sodium hydroxide, potassiumhydroxide, potassium carbonate, sodium hydride, etc.).

On the other hand, the compound II! wherein Q is a group of the formula:--O-- may be prepared by reacting a compound of the formula XVI!:##STR18## wherein Ring B is the same as defined above, with bromomalonicacid diethyl ester in the presence of an acid acceptor (e.g. potassiumcarbonate, etc.) to give a compound of the formula XVII!: ##STR19##wherein Ring B is the same as defined above, followed by reacting thecompound XVII! with the amidine compound XIII! in the presence of a base(e.g. sodium methoxide, etc.) to give a compound of the formula XVIII!:##STR20## wherein the symbols are the same as defined above, further bytreating the compound XVIII! in the same manner as the conversionreaction of the hydroxy groups of the compound XII! into the reactiveresidues wherein Q is a single bond, to give a compound of the formulaXIX!: ##STR21## wherein the symbols are the same as defined above, andby treating the compound XIX! in the same manner as the reaction of thecompound XIV! with the compound XV!.

Moreover, the compound VI! may be prepared by reacting the correspondingcompound II! with a compound of the formula XX!:

    H--Y--Alk--Z.sup.1 --H                                      XX!

wherein Y, Alk and Z¹ are the same as defined above, in the presence ofan acid acceptor (e.g. sodium hydride, etc.).

The starting compound IV! of the present invention may be prepared, forexample, by (i) reacting the compound XIV! or the compound XIX! with thecompound III! in the presence of an acid acceptor (e.g. sodium hydride,etc.) to give a compound XXI!: ##STR22## wherein the symbols are thesame as defined above, reacting the product with sodium azide to give acompound of the formula XXII!: ##STR23## wherein the symbols are thesame as defined above, followed by subjecting the product to catalytichydrogenation, or

by (ii) reacting the compound XIV! or the compound XIX! with ammonia togive a compound of the formula XXIII!: ##STR24## wherein the symbols arethe same as defined above, followed by reacting the product with thecompound III! in the presence of an acid acceptor (e.g. sodium hydride,etc.).

Among the starting compounds IV!, the compound of the formula IV!wherein Z is a group of the formula: --O-- or --NH--, i.e. the compoundof the formula IV-a!: ##STR25## wherein the symbols are the same asdefined above, may be prepared by (i) reacting the compound XIV! or thecompound XIX! with the compound XX! in the presence of an acid acceptor(e.g. sodium hydride, etc.) to give a compound XXIV!: ##STR26## whereinthe symbol are the same as defined above, reacting the product withsodium azide to give a compound of the formula XXV!: ##STR27## whereinthe symbols are the same as defined above, subjecting the product intocatalytic hydrogenation to give a compound XXVI!: ##STR28## wherein thesymbols are the same as defined above, followed by reacting the productwith the compound VIII in the presence of an acid acceptor (e.g. sodiumhydride, etc.), or

by (ii) reacting the compound XXIII! with the compound XX! to give thecompound XXVI!, followed by reacting the product with the compound VII!in the presence of an acid acceptor (e.g. sodium hydride, etc.).

Moreover, the starting compound VIII! may be prepared by (i) reacting acompound of the formula XXVII!: ##STR29## wherein R¹ is the same asdefined above, with the compound XV! in the presence of an acid acceptor(e.g. sodium hydride, etc.) to give a compound of the formula XXVIII!:##STR30## wherein the symbols are the same as defined above, reactingthe product with the compound III! in the presence of an acid acceptor(e.g. sodium hydride, etc.) to give a compound of the formula XXIX!:##STR31## wherein the symbols are the same as defined above, followed byforming a reactive residue by treating the compound XXIX! with ahalogenating agent, or by (ii) reacting the compound XXVII! with thecompound III! in the presence of an acid acceptor (e.g. sodium hydride,etc.) to give a compound of the formula XXX!: ##STR32## wherein thesymbols are the same as defined above, reacting the compound XXX! withsodium azide to give a compound of the formula XXXI!: ##STR33## whereinthe symbols are the same as defined above, subjecting the compound XXXI!to catalytic hydrogenation to give a compound XXXII!: ##STR34## whereinthe symbols are the same as defined above, reacting the compound XXXII!with the compound V! in the presence of an acid acceptor (e.g. sodiumhydride, etc.) to give the compound XXIX!, followed by forming areactive residue by treating with a halogenating agent.

Among the starting compounds VIII!, the compound of the formula VIII!wherein Z is a group of the formula: --O-- or --NH--, i.e. the compoundof the formula VIII-a!: ##STR35## wherein the symbols are the same asdefined above, may be prepared by (i) reacting the compound XXVIII! withthe compound XX! in the presence of an acid acceptor (e.g. sodiumhydride, etc.) to give a compound of the formula XXXIII!: ##STR36##wherein the symbols are the same as defined above, followed by treatingthe compound XXXIII! with a halogenating agent (e.g. N-bromosuccinimide,etc.) to form a reactive residue to give a compound of the formulaXXXIV!: ##STR37## wherein the symbols are the same as defined above,followed by reacting the compound XXXIV! with the compound VII! in thepresence of an acid acceptor (e.g. sodium hydride, etc.), or by (ii)reacting the compound XXVII! with the compound XX! in the presence of anacid acceptor (e.g. sodium hydride, etc.) to give a compound of theformula XXXV!: ##STR38## wherein the symbols are the same as definedabove, reacting the compound XXXV! with sodium azide to give a compoundof the formula XXXVI!: ##STR39## wherein the symbols are the same asdefined above, followed by subjecting the compound XXXVI! to catalytichydrogenation to give a compound of the formula XXXVII!: ##STR40##wherein the symbols are the same as defined above, reacting the compoundXXXVII! with the compound V! to give a compound of the formula XXXVIII!:##STR41## wherein the symbols are the same as defined above, treatingthe compound XXXVIII! with a halogenating agent (e.g. bromine, etc.) toform a reactive residue to give the compound XXXIV!, followed byreacting the compound XXXIV! with the compound VII! in the presence ofan acid acceptor (e.g. sodium hydride, etc.).

Throughout the present specification and claims, the lower alkyl group,the lower alkythio group, the lower alkylamino group, the lower alkoxygroup, the lower alkylenedioxy group, the lower alkylsulfinyl group, thelower alkylsulfonyl group and the lower alkylene group mean ones having1 to 6 carbon atoms, especially ones having 1 to 4 carbon atoms,respectively. The lower alkenyl group, the lower alkanoyl group, thelower alkanoylamino group, the lower alkoxycarbonyl group, the loweralkynyl group, the lower alkenyloxy group, the N-lower alkylcarbamoyloxygroup, the N-lower alkoxyiminomethyl group, the N-loweralkylaminocarbonyl group and the lower alkenylene group mean ones having2 to 7 carbon atoms, especially ones having 2 to 5 carbon atoms,respectively. The cycloalkyl group means ones having 3 to 8 carbonatoms, especially having 3 to 6 carbon atoms. The halogen atom ischlorine, bromine, fluorine, or iodine.

The present invention is illustrated in more detail by the followingExamples and Reference Examples, but should not be construed to belimited thereto.

EXAMPLE 1

To a stirred solution of pyridine-2-methanol (130 mg) indimethylacetamide (0.5 ml) is added gradually with stirring sodiumhydride (62.7% dispersion-type, 60 mg) under ice-cooling, and thereto isadded4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide(100 mg). The mixture is reacted at 100° C. for 30 minutes, and cooled.The pH value of the mixture is adjusted to pH 8 with saturated aqueousammonium chloride solution. The mixture is extracted with ethyl acetate,and the extract is washed, dried, and concentrated to dryness underreduced pressure. The residue is crystallized from ethyl acetate to give4-tert-butyl-N-{5-(3-methoxyphenoxy)-6-(2-pyridinylmethoxy)pyrimidin-4-yl}benzenesulfonamide(110 mg) as crystals.

M.p. 206°-207.5° C.

EXAMPLES 2-18

The corresponding starting compounds are treated in the same manner asin Example 1 to give the compounds as listed in Tables 1-3.

                  TABLE 1                                                         ______________________________________                                         ##STR42##                                                                    Ex.                                                                           No.  AlkZR                  Physical Properties                               ______________________________________                                              ##STR43##             M.p. 194-194° C.                           3                                                                                   ##STR44##             M.p. 129-130° C.                           4                                                                                   ##STR45##             M.p. 153.5-154° C.                         5                                                                                   ##STR46##             M.p. 159-160.5° C.                         6                                                                                   ##STR47##             M.p. 118.5-120° C.                         7                                                                                   ##STR48##             M.p. 148-149.5° C.                         8                                                                                   ##STR49##             M.p. 130-131° C.                           ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Ex.                                                                                 ##STR50##                                                               No.  AlkZR                 Physical Properties                                ______________________________________                                              ##STR51##            M.p. 167.5-169.5° C.                        10                                                                                  ##STR52##            M.p. 197-199.5° C.                          11                                                                                  ##STR53##            M.p. 249.5-251.5° C.                        12                                                                                  ##STR54##            M.p. 118.5-120° C.                          13                                                                                  ##STR55##            M.p. 154.5-155.5° C.                        14                                                                                  ##STR56##            M.p. 179.5-180° C.                          15                                                                                  ##STR57##            M.p. 183.5-184.5° C.                        ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________     ##STR58##                                                                    Ex. No.                                                                            AlkZR                  Physical Properties                               __________________________________________________________________________    16                                                                                  ##STR59##             M.p.: 168-169° C.                          17                                                                                  ##STR60##             M.p.: 153-154° C.                          18                                                                                  ##STR61##             M.p.: 118-119° C.                          __________________________________________________________________________

EXAMPLE 19

(1) After treating4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)-pyrimidin-4-yl}benzenesulfonamideand 2-aminoethanol in the same manner as in Example 1, the precipitatedcrystals are converted into a hydrochloride thereof to giveN-{6-(2-aminoethoxy)-5-(3-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamidehydrochloride (Compound A).

On the other hand, the mother liquor is purified by silica gel columnchromatography (solvent; chloroform/methanol/acetic acid=10:1:0.3) andrecrystallized from chloroform/diisopropyl ether to give4-tert-butyl-N-{6-(2-hydroxyethylamino)-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide(Compound B).

Compound A: M.p. 201.5°-202° C.

Compound B: M.p. 161°-163° C.

(2) A mixture of Compound A (150 mg), 2-chloropyrimidine (61 mg),potassium carbonate (122 mg) and dimethylacetamide (1.5 ml) is heatedwith stirring at 100° C. for three days. The reaction solution isdiluted with aqueous ammonium chloride solution, and extracted withethyl acetate. The extract is washed and dried. The solvent isevaporated to remove the solvent, and the residue is purified by silicagel column chromatography (solvent; chloroform/methanol=100:1) andfurther recrystallized from ethyl acetate/n-hexane to give4-tert-butyl-N-5-(3-methoxyphenoxy)-6-{2-(2-pyrimidinylamino)ethoxy}-pyrimidin-4-yl!benzenesulfonamidehydrate (135 mg) as crystals.

M.p. 101°-102° C. (decomposed)

EXAMPLE 20

To a solution of Compound B (116 mg) obtained in Example 19-(1) indimethylacetamide (2 ml) is added sodium hydride (60% dispersion-type,33 mg), and thereto is added 2-chloropyrimidine (40 mg). The reactionsolution is stirred at room temperature overnight, and the mixture istreated with saturated aqueous ammonium chloride solution, and extractedwith ethyl acetate. The ethyl acetate layer is washed, dried, andevaporated to remove the solvent. The residue is purified by silica gelcolumn chromatography (solvent; chloroform/methanol=20:1), andcrystallized from chloroform/diisopropyl ether to give 4-tert-butyl-N-5-(3-methoxyphenoxy)-6-{2-(pyrimidin-2-yloxy)ethylamino}pyrimidin-4-yl!benzenesulfonamide(125 mg) as crystals.

M.p. 147.5°-149° C.

EXAMPLE 21

To a solution of4-tert-butyl-N-{6-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide(250 mg) in dimethylacetamide (5 ml) is added sodium hydride (60%dispersion-type, 64 mg) at room temperature, and the mixture is stirredfor 20 minutes. To the reaction solution is added5-bromo-2-chloropyrimidine (133 mg), and the mixture is stirred at roomtemperature for 18 hours. The reaction solution is poured intoice-water, and the mixture is neutralized with saturated aqueousammonium chloride solution and extracted with ethyl acetate. The ethylacetate layer is washed, dried, and evaporated to remove the solvent.The residue is purified by silica gel column chromatography (solvent;chloroform/methanol=40:1) to give crude crystals, which arerecrystallized from ethyl acetate/diisopropyl ether to give N--6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(280 mg) as crystals.

M.p. 168°-168.5° C.

EXAMPLES 22-75

The corresponding starting compounds are treated in the same manner asin Example 21 to give the compounds as listed in Tables 4-11.

                                      TABLE 4                                     __________________________________________________________________________     ##STR62##                                                                    Ex. No.                                                                             R                Physical Properties                                    __________________________________________________________________________    22                                                                                   ##STR63##       M.p. 128-129.5° C.                              23                                                                                   ##STR64##       M.p. 130.5-132° C.                              24                                                                                   ##STR65##       M.p. 140.5-141.5° C.                            25                                                                                   ##STR66##       M.p. 156-157° C.                                26                                                                                   ##STR67##       M.p. 142-142.5° C.                              27                                                                                   ##STR68##       M.p. 146.5-147° C.                              28                                                                                   ##STR69##       M.p. 147.5-148.5° C.                            29                                                                                   ##STR70##       M.p. 166-166.5° C.                              __________________________________________________________________________

                  TABLE 5                                                         ______________________________________                                         ##STR71##                                                                    Ex.                              Physical                                     No.  Alk       R                 Properties                                   ______________________________________                                        30   (CH.sub.2).sub.2                                                                         ##STR72##        M.p. 132-134.5° C.                    31   (CH.sub.2).sub.2                                                                         ##STR73##        M.p. 108-109° C.                      32   (CH.sub.2).sub.2                                                                         ##STR74##        M.p. 195.5-196° C.                    33   (CH.sub.2).sub.2                                                                         ##STR75##        M.p. 140.5-142° C.                    34   (CH.sub.2).sub.2                                                                         ##STR76##        M.p. 100.5-101° C.                    35   (CH.sub.2).sub.2                                                                         ##STR77##        M.p. 115.5-118° C.                    36   (CH.sub.2).sub.3                                                                         ##STR78##        M.p. 117-118.5° C.                    37   (CH.sub.2).sub.2                                                                         ##STR79##        M.p. 122-125° C.                      ______________________________________                                    

                                      TABLE 6                                     __________________________________________________________________________     ##STR80##                                                                    Ex. No.                                                                             R                 Physical Properties                                   __________________________________________________________________________    38                                                                                   ##STR81##        M.p. 133.5-135.5° C.                           39                                                                                   ##STR82##        M.p. 159-160° C.                               40                                                                                   ##STR83##        M.p. 113-114° C.                               41                                                                                   ##STR84##        M.p. 160-161° C.                               42                                                                                   ##STR85##        M.p. 153.5-154.5° C.                           43                                                                                   ##STR86##        M.p. 122-123° C.                               44                                                                                   ##STR87##        M.p. 181.5-182.5° C.                           __________________________________________________________________________

                  TABLE 7                                                         ______________________________________                                         ##STR88##                                                                    Ex. No.  R              Physical Properties                                   ______________________________________                                        45                                                                                      ##STR89##     M.p. 181.5-182.5° C.                           46                                                                                      ##STR90##     M.p. 156-157° C.                               47                                                                                      ##STR91##     M.p. 186-187° C.                               ______________________________________                                    

                                      TABLE 8                                     __________________________________________________________________________     ##STR92##                                                                    Ex. No.                                                                           Ring A       R          Physical Properties                               __________________________________________________________________________    48                                                                                 ##STR93##                                                                                  ##STR94## M.p 167-168° C. Sodium salt: M.p.                                      238° C.˜ (decomp) Potassium                                      salt: M.p. >300° C.                        49                                                                                 ##STR95##                                                                                  ##STR96## M.p 133-135° C.                            50                                                                                 ##STR97##                                                                                  ##STR98## M.p. 168-169° C.                           51                                                                                 ##STR99##                                                                                  ##STR100##                                                                              M.p. 143-144° C.                           52                                                                                 ##STR101##                                                                                 ##STR102##                                                                              M.p. 160-161° C.                           53                                                                                 ##STR103##                                                                                 ##STR104##                                                                              M.p. 194.5-195.5° C. Sodium salt: M.p.                                 165° C.˜                             54                                                                                 ##STR105##                                                                                 ##STR106##                                                                              M.p. 188-189°0 C.                          55                                                                                 ##STR107##                                                                                 ##STR108##                                                                              M.p. 169.5-170.5° C. Sodium salt: M.p.                                 218° C.˜ (decomp)                    __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________     ##STR109##                                                                   Ex. No.                                                                           R                  Physical Properties                                    __________________________________________________________________________    56                                                                                 ##STR110##        M.p. 163-165° C.                                57                                                                                 ##STR111##        M.p. 172-173° C.                                58                                                                                 ##STR112##        M.p. 208.5-209.5° C.                            59                                                                                 ##STR113##        M.p. 178.5-179.5° C.                            60                                                                                 ##STR114##        M.p. 194-194.5° C.                              61                                                                                 ##STR115##        M.p. 169-170° C.                                __________________________________________________________________________

                                      TABLE 10                                    __________________________________________________________________________     ##STR116##                                                                   Ex. No.                                                                           R                     Physical Properties                                 __________________________________________________________________________    62                                                                                 ##STR117##           M.p. 163-163.5° C.                           63                                                                                 ##STR118##           M.p. 180-182° C.                             64                                                                                 ##STR119##           M.p. 188.5-189° C. Sodium salt: M.p.                                   148° C.˜                               65                                                                                 ##STR120##           M.p. 138.5-139.5° C.                         66                                                                                 ##STR121##           M.p. 285° C.˜                          67                                                                                 ##STR122##           M.p. 203-204.5° C.                           68                                                                                 ##STR123##           M.p. 147-148° C.                             69                                                                                 ##STR124##           M.p. 177-180° C.                             70                                                                                 ##STR125##           M.p. 144-146° C.                             __________________________________________________________________________

                                      TABLE 11                                    __________________________________________________________________________     ##STR126##                                                                   Ex. No.                                                                           R                     Physical Properties                                 __________________________________________________________________________    71                                                                                 ##STR127##           M.p. 190-191° C.                             72                                                                                 ##STR128##           M.p. 177-178° C.                             73                                                                                 ##STR129##           M.p. 199-200° C.                             74                                                                                 ##STR130##           M.p. 152-156° C.                             75                                                                                 ##STR131##           M.p. 222-225° C.                             __________________________________________________________________________

EXAMPLE 76

A mixture of 6-2-(5-bromopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-amine(150 mg), 4-tert-amylbenzenesulfonyl chloride (184 mg), 96% potassiumhydroxide (powder, 300 mg), tetrabutylammonium hydrogen sulfate (34 mg)and toluene (10 ml) is stirred at room temperature overnight. Themixture is diluted with saturated aqueous ammonium chloride solution,and extracted with ethyl acetate. The ethyl acetate layer is washed,dried, and evaporated to remove the solvent. The residue is purified bysilica gel column chromatography (solvent; chloroform/ethylacetate=5:1), and recrystallized from hexane/ethyl acetate to give4-tert-amyl-N-{6-2-(5-bromopyridin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(188 mg).

M.p. 153.5°-154.5° C.

IR (nujol, cm⁻¹): 3270, 1570, 1570, 1550

FABMS (m/z): 614, 612 (MH⁺)

EXAMPLES 77-82

The corresponding starting compounds are treated in the same manner asin Example 76 to give the compounds as listed in Table 12.

                                      TABLE 12                                    __________________________________________________________________________     ##STR132##                                                                   Ex. No.                                                                           Ring A       R.sup.1  Physical Properties                                 __________________________________________________________________________    77                                                                                 ##STR133##                                                                                 ##STR134##                                                                            M.p. 103-106° C.                             78                                                                                 ##STR135##  H        M.p. 207.5-208° C.                           79                                                                                 ##STR136##  H        M.p. 180.5-182° C.                           80                                                                                 ##STR137##  H        M.p. 191.5-192.5° C.                         81                                                                                 ##STR138##  H        M.p. 216.5-217.5° C.                         82                                                                                 ##STR139##  H        M.p. 208-209° C.                             __________________________________________________________________________

EXAMPLE 83

A mixture of 6-2-(5-bromopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-amine(150 mg), 4-bromobenzenesulfonyl chloride (191 mg), sodium iodide (112mg), sodium hydride (60% dispersion-type, 45 mg) and tetrahydrofuran (5ml) is stirred at room temperature overnight. To the mixture are added4-bromobenzenesulfonyl chloride (191 mg) and sodium hydride (60%dispersion-type, 45 mg), and the mixture is refluxed overnight. Aftercooling, the reaction solution is treated with saturated ammoniumchloride solution, and extracted with ethyl acetate. The ethyl acetatelayer is washed, dried, and evaporated to remove the solvent. Theresidue is purified by preparative tin layer chromatography (solvent;chloroform/ethyl acetate=10:1) to give 4-bromo-N-{6-2-(5-bromopydmidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(85 mg).

M.p. 217°-218° C.

IR (nujol, cm⁻¹): 2800-2400, 1575, 1560

FABMS (m/z): 624, 622, 620 (MH⁺)

EXAMPLE 84

A mixture of N-{5-bromo-6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(100 mg), 3,4-dimethoxyphenyltributyltin (220 mg),bis(triphenylphsophine)palladium (II) chloride (26 mg), copper (I)chloride (11 mg), a few crystals of 2,6-di-tert-butylcrezol and dioxane(5 ml) is refluxed for 1.5 hour. After cooling, the reaction solution isdiluted with ethyl acetate and aqueous potassium fluoride solution, andthe mixture is stirred at room temperature for 30 minutes. The insolublematerials are removed by filtration, and the filtrate is acidified with10% hydrochloric acid, and the mixture is extracted with ethyl acetate.The ethyl acetate layer is washed, dried, and evaporated to remove thesolvent. The residue is purified by preparative thin layerchromatography (solvent; chloroform/ethyl acetate=3:1), andrecrystallized from ethyl acetate/diisopropyl ether to give4-tert-butyl-N-{5-(3,4-dimethoxyphenyl)-6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!-pyrimidino4-yl}benzenesulfonamide(82 mg).

M.p. 170.5°-171.5° C.

IR (nujol, cm⁻¹): 3200, 1590, 1570, 1520, 1510

EXAMPLES 85-95

The corresponding starting compounds are treated in the same manner asin Example 84 to give the compounds as listed in Tables 13-14.

                                      TABLE 13                                    __________________________________________________________________________     ##STR140##                                                                   Ex. No.                                                                           Ring B                   Physical Properties                              __________________________________________________________________________    85                                                                                 ##STR141##              M.p. 166-167° C.                          86                                                                                 ##STR142##              M.p. 126-129° C.                          87                                                                                 ##STR143##              M.p. 150-151° C.                          88                                                                                 ##STR144##              M.p. 171-172° C.                          89                                                                                 ##STR145##              M.p. 165.5-166.5° C.                      90                                                                                 ##STR146##              M.p. 150-152° C.                          __________________________________________________________________________

                                      TABLE 14                                    __________________________________________________________________________     ##STR147##                                                                   Ex. No.                                                                           Ring B                  Physical Properties                               __________________________________________________________________________    91                                                                                 ##STR148##             M.p. 144.5-145.5° C.                       92                                                                                 ##STR149##             M.p. 170-171° C.                           93                                                                                 ##STR150##             M.p. 180.5-181.5° C.                       94                                                                                 ##STR151##             M.p. 157.5-159.5° C.                       95                                                                                 ##STR152##             M.p. 164-166° C.                           __________________________________________________________________________

EXAMPLE 96

A mixture of N-6-{2-(5-bromopyridin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(150 mg), tributylphenyltin (131 mg), bis(triphenylphosphine)palladium(II) chloride (8.5 mg) and dioxane (4 ml) is refluxed for 12 hours. Thereaction solution is diluted with ethyl acetate, and treated withaqueous 10% potassium fluoride solution. The insoluble materials areremoved by filtration, and the ethyl acetate layer is collected, washedwith water, dried, and evaporated to remove the solvent. The residue ispurified by silica gel column chromatography (solvent; chloroform), andrecrystallized from ethyl acetate/diisopropyl ether to give4-tert-butyl-N-5-(3-methoxyphenoxy)-6-{2-(5-phenylpyrimidin-2-yloxy)ethoxy}pyrimidin-4-yl!benzenesulfonamide(85 mg) as crystals.

M.p. 160°-161° C.

EXAMPLES 97-118

N-6-{2-(5-Bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamideand the corresponding starting compounds are treated in the same manneras in Example 96 to give the compounds as listed in Tables 15-17.

                  TABLE 15                                                        ______________________________________                                         ##STR153##                                                                   Ex. No.                                                                             R                    Physical Properties                                ______________________________________                                        97                                                                                   ##STR154##          M.p. 197-198° C. Sodium salt: M.p.                                     254-256° C. (decomp)                        98                                                                                   ##STR155##          M.p. 185.5-186.5° C.                        99                                                                                   ##STR156##          M.p. 180.5-182° C. Sodium salt: M.p.                                   244-250° C. (decomp)                        100                                                                                  ##STR157##          M.p. 196-197° C. Sodium salt: M.p.                                     256-257° C.                                 101                                                                                  ##STR158##          M.p. 187-189° C.                            102                                                                                  ##STR159##          M.p. 166-168° C.                            103                                                                                  ##STR160##          M.p. 190-190.5° C.                          ______________________________________                                    

                  TABLE 16                                                        ______________________________________                                         ##STR161##                                                                   Ex.                                                                           No.  R                     Physical Properties                                ______________________________________                                        104                                                                                 ##STR162##           M.p. 186-187.5° C.                          105                                                                                 ##STR163##           M.p. 186-187.5° C.                          106                                                                                 ##STR164##           M.p. 219.5-221° C.                          107                                                                                 ##STR165##           M.p. 194.5-195.5° C.                        108                                                                                 ##STR166##           M.p. 194.5-196° C.                          109                                                                                 ##STR167##           M.p. 189.5-190.5° C.                        110                                                                                 ##STR168##           M.p. 182-183° C.                            111                                                                                 ##STR169##           M.p. 126.5-128.5° C.                        ______________________________________                                    

                  TABLE 17                                                        ______________________________________                                         ##STR170##                                                                   Ex. No.                                                                              R                   Physical Properties                                ______________________________________                                        112                                                                                   ##STR171##         M.p. 181-182° C.                            113                                                                                   ##STR172##         M.p. 148° C.˜                         114                                                                                   ##STR173##         M.p. 219-220° C.                            115                                                                                   ##STR174##         M.p. 196-197° C.                            116                                                                                   ##STR175##         M.p. 164-165.5° C.                          117                                                                                   ##STR176##         M.p. 168-171° C.                            118                                                                                   ##STR177##         M.p. 176.5-177.5° C.                        ______________________________________                                    

EXAMPLE 119

N-6-{2-(5-Bromopyrimidin-2-yloxy)ethoxy}-5-(2-methoxyphenoxy)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamideand the corresponding starting compounds are treated in the same manneras in Example 96 to give 4-tert-butyl-N-5-(2-methoxyphenoxy)-6-{2-(5-(2-thienyl)pyrimidin-2-yloxy)ethoxy}pyrimidin-4-yl!benzenesulfonamide.

M.p. 185.5°-186.5° C.

EXAMPLE 120

A mixture of 4-tert-butyl-N-5-(3-methoxyphenoxy)-6-{2-(2-methylthiopyrimidin-4-yloxy)ethoxy}pyrimidin-4-yl!benzenesulfonamide(250 mg), Raney-nickel (W-2) (2 g) and ethanol (5 ml) is stirred at roomtemperature overnight, and the mixture is refluxed for four hours.Raney-nickel is removed by filtration, and washed with ethanol andacetic acid. The filtrate is concentrated under reduced pressure, andthe residue is extracted with ethyl acetate. The ethyl acetate layer iswashed, dried, and evaporated to remove the solvent. The residue ispurified by silica gel column chromatography (solvent;chloroform/methanol=10:1), and recrystallized from ethylacetate/n-hexane to give 4-tert-butyl-N-5-(3-methoxyphenoxy)-6-{2-(pyrimidin-4-yloxy)ethoxy}pyrimidin-4-yl!benzenesulfonamide(76 mg) as crystals.

M.p. 149°-150.5° C.

EXAMPLE 121

A mixture of 4-tert-butyl-N-6-{2-(6-chloropyridazin-3-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl!benzenesulfonamide(150 mg), 10% palladium-carbon (30 mg), triethylamine (52 mg), methanol(8 ml) and tetrahydrofuran (6 ml) is stirred at room temperature forfive hours under hydrogen atmosphere (1 atm), and the mixture isfiltered to remove the catalyst. The filtrate is concentrated to drynessunder reduced pressure. The residue is treated with aqueous citric acidsolution, and extracted with chloroform. The extract is washed, driedand evaporated to remove the solvent. The residue is recrystallized fromethyl acetate/diisopropyl ether to give 4-tert-butyl-N-5-(3-methoxyphenoxy)-6-{2-(pyridazin-3-yloxy)ethoxy}pyrimidin-4-yl!benzenesulfonamide(111 mg) as crystals.

M.p. 169.5°-170° C.

EXAMPLE 122

4-tert-buyl-N-5-(3-methoxyphenoxy)-6-{2-(1-methyl-4,5-dibromoimidazol-2-yloxy)ethoxy}pyrimidin-4-yl!benzenesulfonamideand the corresponding starting compounds are treated in the same manneras in Example 121 to give 4-tert-buyl-N-5-(3-methoxyphenoxy)-6-{2-(1-methylimidazol-2-yloxy)ethoxy}pyrimidin-4-yl!benzenesulfonamide.

M.p. 124°-126° C.

EXAMPLE 123

(1) To a solution of 2-mercaptoethanol (1.31 g) in dimethylacetamide (15ml) is added sodium hydride (62.3% dispersion-type, 520 mg) under argonatmosphere. Five minutes later, to the mixture is added4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)pydmidin-4-yl}benzenesulfonamide(1.5 g), and the mixture is reacted under argon atmosphere at 70° C. fortwo hours, at 100° C. for three hours, and further reacted at 130° C.for two hours. The reaction solution is treated with hydrochloric acid,and extracted with ethyl acetate. The ethyl acetate layer is washed,dried, and evaporated to remove the solvent. The residue is purified bysilica gel column chromatography (solvent; chloroform/methanol=70:1),and recrystallized from ethyl acetate/n-hexane to give4-tert-butyl-N-{6-(2-hydroxyethylthio)-5-(3-methoxyphenoxy)pyrimidin-4-yl}-benzenesulfonamide(1.14 g) as crystals.

M.p. 149.5°-150.5° C.

(2) A mixture of the above product (200 mg), 2-chloropyrimidine (61 mg),sodium hydride (62.3% dispersion-type, 47 mg), and dimethylacetamide (3ml) is stirred at room temperature overnight. The mixture is treatedwith aqueous ammonium chloride solution, and extracted with ethylacetate. The ethyl acetate layer is washed, dried, and evaporated toremove the solvent. The residue is purified by silica gel columnchromatography (solvent; chloroform/methanol=50:1) and recrystallizedfrom ethyl acetate/n-hexane to give 4-tert-butyl-N-5-(3-methoxyphenoxy)-6-{2-(pyrimidin-2-yloxy)ethylthio}-pyrimidin-4-yl!benzenesulfonamide(191 mg) as crystals.

M.p. 167.5°-168° C.

EXAMPLE 124

A mixture of 4-tert-butyl-N-6-{2-(5-(1-ethoxyethenyl)pyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl!benzenesulfonamide(1.022 g), 10% hydrochloric acid (1 ml) and acetone (20 ml) is reactedat room temperature for four hours. The pH value of the reactionsolution is adjusted to pH 6 with aqueous sodium hydrogen carbonatesolution, and the mixture is evaporated to remove the solvent. To theresidue are added aqueous ammonium chloride solution and ethyl acetate,and the ethyl acetate layer is collected. The ethyl acetate layer iswashed, dried, and evaporated to remove the solvent. The residue ispurified by silica gel column chromatography (solvent; ethylacetate/n-hexane=1:1˜ethyl acetate), and recrystallized from ethylacetate/n-hexane to give N-6-{2-(5-acetylpyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(849 mg).

M.p. 142.5°-144° C.

EXAMPLE 125

To a mixture of N-6-{2-(5-acetylpyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(756 mg), tetrahydrofuran (10 ml) and isopropyl alcohol (10 ml) is addedwith stirring sodium borohydride (48 mg) under ice-cooling, and themixture is stirred for 40 minutes under ice-cooling. To the reactionsolution is further added sodium borohydride (14 mg), and the mixture isstirred for 30 minutes. The mixture is diluted with water, and extractedwith ethyl acetate. The ethyl acetate layer is washed, dried, andconcentrated to dryness under reduced pressure. The residue is purifiedby silica gel column chromatography (solvent;chloroform/methanol=40:1˜20:1), and recrystallized from ethylacetate/n-hexane to give 4-tert-butyl-N-6-{2-(5-(1-hydroxyethyl)pyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl!benzenesulfonamide(571 mg) as crystals.

M.p. 133°-135° C.

EXAMPLE 126

The corresponding starting compounds are treated in the same manner asin Example 125 to give 4-tert-butyl-N-5-(4-hydroxymethylphenyl)-6-{2-((5-methylthio)pyrimidin-2-yloxy)ethoxy}pyrimidin-4-yl!benzenesulfonamide.

M.p. 172°-173° C.

EXAMPLE 127

N-6-{2-(4-Acetylphenoxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamideis treated in the same manner as in Example 125 to give 4-tert-butyl-N-6-{2-(4-(1-hydroxyethyl)phenoxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!benzenesulfonamide.

M.p. 176°-178° C.

EXAMPLE 128

To a solution of 4-tert-butyl-N-6-{2-(5-(1-hydroxyethyl)pyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl!benzenesulfonamide(150 mg) in methylene chloride (3 ml) is added thionyl chloride (90 mg),and the mixture is reacted at room temperature for 0.5 hour. Thereaction solution is concentrated to dryness under reduced pressure, andto the residue are added 10% palladium-carbon (30 mg), triethylamine (76mg) and ethanol (3 ml), and the mixture is stirred at room temperaturefor two hours under hydrogen atmosphere (1 atm). The catalyst is removedby filtration, and the filtrate is concentrated to dryness under reducedpressure. The residue is extracted with ethyl acetate, and the ethylacetate layer is washed, dried, and evaporated to remove the solvent.The residue is purified by silica gel column chromatography (solvent;chloroform/ethyl acetate=10:1), and recrystallized from ethylacetate/n-hexane to give 4-tert-butyl-N-6-{2-(5-ethylpyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl!benzenesulfonamide(137 mg) as crystals.

M.p. 158.5°-159.5° C.

EXAMPLE 129

To a solution of N-6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(300 mg) in tetetrahydrofuran (10 ml) is added a 1.6M solution ofn-butyl lithium in n-hexane (0.75 ml) at -78° C. The mixture is stirredat -78° C. for 5 minutes, and thereto is added a solution of acetone (58mg) in tetrahydrofuran (1 ml), and the mixture is warmed to roomtemperature. The mixture is treated with aqueous ammonium chloridesolution, and extracted with ethyl acetate. The ethyl acetate layer iswashed, dried, and evaporated to remove the solvent. The residue ispurified by silica gel column chromatography (solvent; chloroform/ethylacetate=2:1˜1:1), and recrystallized from ethyl acetate/n-hexane to give4-tert-butyl-N-6-{2-(5-(1-hydroxy-1-methylethyl)primidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!benzenesulfonamide(88 mg) as crystals.

M.p. 149.5°-150.5° C.

EXAMPLE 130

N-6-{2-(5-Bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamideand benzaldehyde are treated in the same manner as in Example 129 togive 4-tert-butyl-N-6-{2-(5-(α-hydroxybenzyl)primidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!-benzenesulfonamide.

M.p. 183°-185° C.

EXAMPLES 131-133

A mixture of N-6-{2-(4-bromophenoxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(600 mg), (1-ethoxyvinyl)tributyltin (680 mg),bis(triphenylphosphine)palladium (II) chloride (35.5 mg) and dioxane (24ml) is refluxed for 18 hours. The mixture is diluted with ethyl acetate,and thereto is added 10% aqueous potassium fluoride solution, and theprecipitated crystals are removed by filtration. The filtrate isextracted with ethyl acetate, and the ethyl acetate layer is washed,dried, and concentrated to dryness under reduced pressure. The residueis purified by silica gel column chromatography (solvent; n-hexane/ethylacetate=5:1˜3:1˜1:1), and the obtained compounds are each recrystallizedfrom ethyl acetate/diisopropyl ether to give4-tert-butyl-N-{5-(4-methylphenyl)-6-(2-phenoxyethoxy)pyrimidin-4-yl}benzenesulfonamide(Compound A) (42 mg), N-6-{2-(4-acetylphenoxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(Compound B) (242 mg) and 4-tert-butyl-N-6-{2-(4-ethoxycarbonylphenoxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!benzenesulfonamide(Compound C) (58 mg), respectively.

Compound A: M.p. 186.5°-187.5° C.

Compound B: M.p. 205°-206.5° C.

Compound C: M.p. 199.5°-200.5° C.

EXAMPLE 134

To a solution of4-tert-butyl-N-{5-(4-methylphenyl)-6-{2-(5-nitropyridin-2-yloxy)ethoxy}pyrimidin-4-yl}benzenesulfonamide(975 mg) in isopropanol/tetrahydrofuran (1:1) (20 ml) is added 10%palladium-carbon (200 mg), and the mixture is stirred at roomtemperature for 1.5 hour under hydrogen atmosphere (1 atm). The catalystis removed by filtration, and the filtrate is concentrated under reducedpressure. The residue is purified by silica gel column chromatography(solvent; chloroform/ethyl acetate=2:1), and recrystallized from ethylacetate/n-hexane to giveN-{6-{2-(5-aminopyridin-2-yl-oxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(829 mg) as crystals.

M.p. 165°-167° C. (decomposed)

EXAMPLE 135

To a solution ofN-{6-{2-(5-aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(150 mg) in pyridine (2 ml) is added a solution of benzoyl chloride (43mg) in methylene chloride (0.4 ml), and the mixture is stirred at roomtemperature for two hours. To the reaction solution is added 10%hydrochloric acid, and the mixture is extracted with ethyl acetate. Theethyl acetate layer is washed, dried and evaporated to remove thesolvent. The residue is recrystallized from ethyl acetate/n-hexane togive N-(6-2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy!pyridin-3-yl)benzamide(161 mg) as crystals.

M.p. 173°-174.5° C.

EXAMPLE 136

N-{6-{2-(5-Aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamideand acetic anhydride are treated in the same manner as in Example 135 togive N- 6-2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy!pyridin-3-yl!-acetamide.

M.p. 175°-176° C.

EXAMPLE 137

N-{6-{2-(5-Aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamideand pivaloyl chloride are treated in the same manner as in Example 135to give N- 6-2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy!pyridin-3-yl!pivalamide.

M.p. 140°-141° C.

EXAMPLE 138

A mixture of 4-tert-butyl-N-{6-2-(4-benzyloxyphenoxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzensulfonamide(3.95 g), 10% palladium-carbon (1.5 g) and ethanol-tetrahydrofuran (80ml-80 ml) is subjected to catalytic hydrogenation at room temperatureunder hydrogen atmosphere (1 atm) for 24 hours. The catalyst is removedby filtration, and the filtrate is concentrated. The residue iscrystallized from ethyl acetate/diisopropyl ether to give4-tert-butyl-N-{6-2-(4-hydroxyphenoxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(3.31 g).

M.p. 161.5°-163° C.

IR (nujol, cm⁻¹): 3260, 1590, 1570

FABMS (m/z): 556 (M⁺ +Na), 534 (MH⁺)

EXAMPLE 139

The compound obtained in Example 62 is treated in the same manner as inExample 138 to give 4-tert-butyl-N-{6-2-(5-hydroxypyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide.

M.p. 186.5°-188° C.

EXAMPLE 140

A mixture of 4-tert-butyl-N-{5-(4-methylphenyl)-6-2-(4-nitrophenoxy)ethoxy!pyrimidin-4-yl}benzenesulfonamide (383 mg), 10%palladium-carbon (50 mg) and ethanol-tetrahydrofuran (6 ml-3 ml) issubjected to catalytic hydrogenation at room temperature under hydrogenatmosphere (1 atm) for two hours. The catalyst is removed by filtration,and the filtrate is concentrated. The residue is purified by silica gelcolumn chromatography (solvent; chloroform/ethyl acetate=10:1), andrecrystallized from ethyl acetate/diisopropyl ether to give N-{6-2-(4-aminophenoxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(358 mg).

M.p. 190°-191° C.

IR (nujol, cm⁻¹): 3440, 3360, 3260, 1740, 1630, 1610

FABMS (m/z): 533 (M H⁺)

EXAMPLE 141

To a solution of N-{6-2-(4-aminophenoxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(100 mg) in tetrahydrofuran (2 ml) are added formic acid (38 mg) and 35%aqueous formaldehyde solution (0.05 ml), and the mixture is stirred at50° C. for three hours. The reaction solution is poured into ice-water,and the mixture is neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The ethyl acetatelayer is washed, dried and evaporated to remove the solvent. The residueis purified by silica gel column chromatography (solvent;chloroform/ethyl acetate=10:1), and recrystallized from ethylacetate/diisopropyl ether to give 4-tert-butyl-N-{6-2-(4-dimethylaminophenoxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(67 mg).

M.p. 142°-145° C.

IR (nujol, cm⁻¹): 3260, 1590, 1570

FABMS (m/z): 561 (MH⁺)

EXAMPLE 142

A mixture of 4-tert-butyl-N-{6-2-(4-cyanophenoxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzensulfonamide(1.31 g), tributyltin azide (1.60 g) and toluene (13 ml) is refluxedunder argon atmosphere for 24 hours. After cooling, ethyl acetate and10% aqueous potassium fluoride solution are added to the reactionsolution. The insoluble materials are removed by filtration, and theethyl acetate layer is concentrated to dryness under reduced pressure.To the residue are added 10% aqueous sodium hydroxide solution anddiethyl ether, and the mixture is stirred at room temperature for 20minutes. The aqueous layer is washed with diethyl ether, and acidifiedwith 10% hydrochloric acid under ice-cooling. The mixture is extractedwith ethyl acetate, and the ethyl acetate layer is washed, dried andevaporated to remove the solvent. The residue is purified by silica gelcolumn chromatography (solvent:chloroform:methanol=100:0˜20:1), andcrystallized from ethyl acetate to give4-tert-butyl-N-{5-(4-methylphenyl)-6-2-(4-(5-tetrazolyl)phenoxy)ethoxy!-pyrimidin-4-yl}benzensulfonamide(1.26 g).

M.p. 165°-166° C.

IR (nujol, cm⁻¹): 3260, 1620, 1580

FABMS (m/z): 586 (MH⁺)

EXAMPLE 143

To a solution of 4-tert-butyl-N-{6-2-(4-hydroxyphenoxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(200 mg) in dimethylformamide (2 ml) is added sodium hydride (60%dispersion-type, 32 mg), and the mixture is stirred at room temperaturefor 30 minutes. To the mixture is added a solution of tert-butylbromoacetate (77 mg) in dimethylformamide (2 ml) under ice-cooling, andthe mixture is stirred at the same temperature for one hour. Thereaction solution is poured into ice-water, and treated with saturatedaqueous ammonium chloride solution, and extracted with ethyl acetate.The ethyl acetate layer is washed, dried and evaporated to remove thesolvent. The residue is purified by silica gel column chromatography(solvent; hexane/ethyl acetate=3:1), and crystallized from ethylacetate/diisopropyl ether to give tert-butyl4-{2-(6-(4-tert-butybenzenesulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy)ethoxy}phenoxyacetate(225 mg ).

M.p. 129.5°-130.5° C.

IR (nujol, cm⁻¹): 3280, 1765, 1590, 1570

FABMS (m/z): 648 (MH⁺)

EXAMPLE 144

To a solution of tert-butyl4-{2-{6-(4-tert-butylbenzenesulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy!ethoxy}phenoxyacetate(1.25 g) in dichloromethane (120 ml) are added anisole (2.09 g) andtrifluoroacetic acid (20 ml) under ice-cooling. The mixture is stirredat room temperature for five hours, washed with water, and extractedwith 10% aqueous sodium hydroxide solution. The aqueous layer is washedwith chloroform, and acidified with 10% hydrochloric acid underice-cooling. The mixture is extracted with ethyl acetate, and theextract is washed, dried, and evaporated to remove the solvent. Theresidue is crystallized from ethyl acetate/diisopropyl ether to give4-{2-6-(4-tert-butylbenzenesulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yl-oxy!ethoxy}phenoxyaceticacid (1.14 9).

M.p. 183°-184.5° C.

IR (nujol, cm⁻¹): 3260, 3240, 1760, 1740, 1710, 1580, 1565

FABMS (m/z): 592 (MH⁺)

EXAMPLE 145

To a solution of 4-tert-butyl-N-{6-2-(4-(1-hydroxyethyl)phenoxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(85 mg) in dichloromethane (3 ml) is added thionyl chloride (54 mg), andthe mixture is stirred for one hour. The reaction solution isconcentrated to dryness under reduced pressure, and the residue isdissolved in ethanol-tetrahydrofuran (6 ml-2 ml). To the mixture isadded triethylamine (45 mg) at room temperature, and the mixture isstirred for three hours. The mixture is evaporated to remove thesolvent, and the residue is dissolved in ethyl acetate, washed, driedand evaporated to remove the solvent. The residue is purified by silicagel column chromatography (solvent; hexane/ethyl acetate=3:1), andrecrystallized from ethyl acetate/diisopropyl ether to give4-tert-butyl-N-{6-2-(4-(1-ethoxyethyl)phenoxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(61 mg).

M.p. 139°-140° C.

IR (nujol, cm⁻¹): 3270, 1610, 1590, 1570

FABMS (m/z): 590 (MH⁺)

EXAMPLE 146

To a solution of N-6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(700 mg) in tetrahydrofuran (15 ml) is added dropwise a 1.6M solution ofn-butyl lithium in n-hexane (1.46 ml) at -78° C. The mixture is stirredat -78° C. for 15 minutes, and thereto is added dimethylformamide (0.28ml), and the reaction solution is reacted at the same temperature for 15minutes. The solution is treated with aqueous ammonium chloridesolution, and acidified with 10% hydrochloric acid, and extracted withethyl acetate. The ethyl acetate layer is washed, dried, and the residueis purified by silica gel column chromatography (solvent;chloroform/ethyl acetate=100:1˜30:1), and recrystallized fromdiisopropyl ether to give 4-tert-butyl-N-6-{2-(5-formylpyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!benzenesulfonamide(198 mg) as crystals.

M.p. 191°-193° C.

FABMS (m/z): 548 (MH⁺)

EXAMPLE 147

To a solution of 4-tert-butyl-N-6-{2-(5-formylpyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!benzenesulfonamide(143 mg) in tetrahydrofuran-isopropanol (4 ml-4 ml) is added sodiumborohydride (13 mg) under ice-cooling, and the mixture is reacted fortwo hours. The mixture is treated with aqueous ammonium chloridesolution, and extracted with ethyl acetate. The ethyl acetate layer iswashed, dried, and evaporated to remove the solvent. The residue ispurified by silica gel column chromatography (solvent;chloroform/methanol=200:1˜50:1), and crystallized from diethyl ether togive 4-tert-butyl-N-6-{2-(5-hydroxymethylpyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl!benzenesulfonamide(96 mg).

M.p. 172°-173° C.

FABMS (m/z): 550 (MH⁺)

EXAMPLE 148

To a suspension of sodium hydride (0.25 g) in tetrahydrofuran (5 ml) isadded dropwise a solution of 4-tert-butyl-N-6-(2-hydroxyethoxy)-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl!benzenesulfonamide(1.00 g) in dimethylacetamide (3 ml) and tetrahydrofuran (10 ml) at roomtemperature, and thereto is added 2-chloro-5-bromopyrimidine (0.56 g),and the mixture is stirred at room temperature for 2.5 hours. Thereaction mixture is acidified with ice-cold diluted hydrochloric acid,and extracted with ethyl acetate. The extract is washed, dried, andevaporated to remove the solvent. The resulting oily product is purifiedby silica gel column chromatography (solvent; chloroform), andcrystallized from n-hexane to give 4-tert-butyl-N-6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl!benzenesulfonamide(1.21 g) as crystals.

M.p. 184°-186° C.

EXAMPLES 149-189

The corresponding starting compounds are treated in the same manner asin Example 148 to give the compounds as listed in Tables 18-25.

                                      TABLE 18                                    __________________________________________________________________________     ##STR178##                                                                   Ex. No.                                                                           R.sup.1  R               Physical Properties                              __________________________________________________________________________    149                                                                                ##STR179##                                                                             ##STR180##     M.p. 154-156° C.                          150                                                                                ##STR181##                                                                             ##STR182##     M.p. 216-218° C. (decomposed)             151                                                                                ##STR183##                                                                             ##STR184##     M.p. 219-221° C.                          152 CH.sub.2 CH.sub.2 CH.sub.3                                                              ##STR185##     M.p. 103-104° C.                          153 CH.sub.2 CH.sub.2 CH.sub.3                                                              ##STR186##     M.p. 143-145° C.                          154                                                                                ##STR187##                                                                             ##STR188##     M.p. 214-215° C.                          __________________________________________________________________________

                  TABLE 19                                                        ______________________________________                                         ##STR189##                                                                   Ex.                              Physical                                     No.  R.sup.1   R                 Properties                                   ______________________________________                                        155                                                                                 ##STR190##                                                                              ##STR191##       M.p. 140-142° C.                      156                                                                                 ##STR192##                                                                              ##STR193##       Amorphous                                    157                                                                                 ##STR194##                                                                              ##STR195##       Amorphous                                    158                                                                                 ##STR196##                                                                              ##STR197##       Amorphous                                    159                                                                                 ##STR198##                                                                              ##STR199##       M.p. 223-232° C.                      160                                                                                 ##STR200##                                                                              ##STR201##       --                                           161                                                                                 ##STR202##                                                                              ##STR203##       --                                           ______________________________________                                    

                  TABLE 20                                                        ______________________________________                                         ##STR204##                                                                   Ex.                              Physical                                     No.  R.sup.1   R                 Properties                                   ______________________________________                                        162                                                                                 ##STR205##                                                                              ##STR206##       M.p. 187-191° C.                      163  CH.sub.3                                                                                 ##STR207##       M.p. 148-149.5° C.                    164                                                                                 ##STR208##                                                                              ##STR209##       M.p. 178-180° C.                      165                                                                                 ##STR210##                                                                              ##STR211##       M.p. 147-149° C.                      166                                                                                 ##STR212##                                                                              ##STR213##       --                                           ______________________________________                                    

                  TABLE 21                                                        ______________________________________                                         ##STR214##                                                                   Ex.                              Physical                                     No.  R.sup.1   R                 Properties                                   ______________________________________                                        167                                                                                 ##STR215##                                                                              ##STR216##       M.p. 199-206° C.                      168                                                                                 ##STR217##                                                                              ##STR218##       M.p. 133-136° C.                      169                                                                                 ##STR219##                                                                              ##STR220##       M.p. 173.5-174.5° C.                  170  CH(CH.sub.3).sub.2                                                                       ##STR221##       M.p. 202-203° C.                      171  CH(CH.sub.3).sub.2                                                                       ##STR222##       M.p. 166-168° C.                      172                                                                                 ##STR223##                                                                              ##STR224##       M.p. 196-197° C.                      173                                                                                 ##STR225##                                                                              ##STR226##       M.p. 209-210° C.                      174                                                                                 ##STR227##                                                                              ##STR228##       M.p. 185-187.5° C.                    175                                                                                 ##STR229##                                                                              ##STR230##       M.p. 169-171.5° C.                    ______________________________________                                    

                  TABLE 22                                                        ______________________________________                                         ##STR231##                                                                   Ex.                              Physical                                     No.  R.sup.1   R                 Properties                                   ______________________________________                                        176                                                                                 ##STR232##                                                                              ##STR233##       M.p. 175-177° C.                      177                                                                                 ##STR234##                                                                              ##STR235##       M.p. 132-141° C.                      ______________________________________                                    

                  TABLE 23                                                        ______________________________________                                         ##STR236##                                                                   Ex.                              Physical                                     No.  R.sup.1   R                 Properties                                   ______________________________________                                        178                                                                                 ##STR237##                                                                              ##STR238##       M.p. 228-229.5° C.                    179                                                                                 ##STR239##                                                                              ##STR240##       M.p. 233.5-234.5° C.                  ______________________________________                                    

                  TABLE 24                                                        ______________________________________                                         ##STR241##                                                                                                     Physical                                    Ex. No.                                                                             R.sup.1   R                 Properties                                  ______________________________________                                        180   H                                                                                        ##STR242##       M.p. 141-142° C.                     181   H                                                                                        ##STR243##       M.p. 183-184.5° C.                   182                                                                                  ##STR244##                                                                              ##STR245##       M.p. 194.5-196° C.                   ______________________________________                                    

                                      TABLE 25                                    __________________________________________________________________________     ##STR246##                                                                   Ex. No.                                                                           Ring A                                                                                       ##STR247##                                                                              Physical Properties                              __________________________________________________________________________    183                                                                                ##STR248##                                                                                  ##STR249##                                                                              M.p. 161-163° C.                          184                                                                                ##STR250##                                                                                  ##STR251##                                                                              M.p. 130-137° C.                          185                                                                                ##STR252##                                                                                  ##STR253##                                                                              M.p. 130-132° C.                          186                                                                                ##STR254##                                                                                  ##STR255##                                                                              M.p. 155-156° C.                          187                                                                                ##STR256##                                                                                  ##STR257##                                                                              M.p. 164-165.5° C.                        188                                                                                ##STR258##                                                                                  ##STR259##                                                                              M.p. 167-170° C.                          189                                                                                ##STR260##                                                                                  ##STR261##                                                                              M.p. 217-218° C.                          __________________________________________________________________________

EXAMPLE 190

A mixture of 4-tert-butyl-N-6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl!benzenesulfonamide(300 mg), 2-thienyltributyltin (670 mg),bis(triphenylphosphine)palladium (II) chloride (16 mg) and dioxane (5ml) is refluxed for 80 minutes. After cooling, the reaction solution isdiluted with ethyl acetate, and thereto is added 10% aqueous potassiumfluoride solution. The mixture is stirred at room temperature for onehour, and the reaction solution is washed, dried, and evaporated toremove the solvent. The residue is purified by silica gel columnchromatography (solvent; n-hexane/ethyl acetate=30:1˜10:1), andcrystallized from methylene chloride/n-hexane to give 4-tert-butyl-N-6-{2-(5-(2-thienyl)pyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl!-benzenesulfonamide(209 mg) as crystals.

M.p. 165°-166° C.

EXAMPLE 191

The product obtained in Example 150 and 2-pyridyltributyltin are treatedin the same manner as in Example 190 to give 4-tert-butyl-N-6-{2-(5-(2-pyridyl)pyrimidin-2-yloxy)ethoxy}-5-(2-methoxyphenoxy)-2-(2-pyrimidyl)pyrimidin-4-yl!benzenesulfonamide.

M.p. 149°-157° C.

EXAMPLE 192

(1) To a solution ofN-{6-chloro-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(1.05 g) and 2-(4-acetylphenoxy)ethanol (728 mg) in dimethylacetamide(12 ml) is added sodium hydride (240 mg) under ice-cooling, and themixture is stirred at room temperature overnight. The reaction solutionis acidified with 10% hydrochloric acid, and extracted with ethylacetate. The extract is washed, dried, and evaporated to remove thesolvent. The residue is purified by silica gel column chromatography(solvent; chloroform/acetonitrile=2:1), and recrystallized from ethylacetate/n-hexane to give N-6-{2-(4-acetylphenoxy)ethoxy}-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(482 mg) as crystals.

M.p. 169°-172° C.

(2) To a mixture of the above product (197 mg), isopropyl alcohol (2 ml)and tetrahydrofuran (2 ml) is added sodium borohydride (26 mg) underice-cooling, and the mixture is stirred at the same temperature for twohours. After the reaction is complete, the mixture is evaporated toremove the solvent, and the residue is acidified with 10% hydrochloricacid, and extracted with ethyl acetate. The extract is washed, dried,and evaporated to remove the solvent. The residue is purified by silicagel column chromatography (solvent; chloroform/acetonitrile=1:1) andrecrystallized from ethyl acetate/n-hexane to giveN-{6-{2-(4-(1-hydroxyethyl)phenoxy)ethoxy}-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(85 mg) as crystals.

M.p. 191°-194° C.

EXAMPLE 193

N-{6-Chloro-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamideand 2-(4-bromophenoxy)ethanol are treated in the same manner as inExample 192-(1) to giveN-{6-{2-(4-bromophenoxy)ethoxy}-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide.

M.p. 251°-256° C.

EXAMPLE 194

To a stirred solution of sodium 4-tert-butyl-N-{6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(1.0 g) in chloroform (10 ml) is added 3-chloroperbenzoic acid (41 2 mg)at 0° C., and the reaction mixture is stirred at 0° C. for one hour, andstirred at room temperature overnight. The reaction mixture is dilutedwith saturated aqueous sodium hydogen carbonate solution, and extractedthree times with chloroform. The combined organic layer is washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (solvent; chloroform/ethyl acetate=2:1˜1:1), and thedesired fractions are recrystallized from ethyl acetate/n-hexane to give4-tert-butyl-N-{6-2-(5-methylsulfonylpyrimidin-2-yl-oxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(Compound A) (91 mg) and 4-ted-butyl-N-{6-2-(5-methylsulfinylpyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(Compound B) (601 mg).

Compound A: Colorless crystalline powder M.p. 170°-172° C.

Compound B: Colorless crystalline powder M.p. 206.5°-208° C.

EXAMPLE 195

(1) A solution of 4-tert-butyl-N-{6-2-(5-methylsulfinylpyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(471 mg) in trifluoroacetic anhydride (5 ml) and methylene chloride (5ml) is refluxed for 30 minutes, and the mixture is evaporated to removethe solvent. The residue is dissolved in methanol/triethylamine (1:1)(20 ml), and concentrated to dryness under reduced pressure. The residueis dissolved in chloroform, washed with saturated aqueous ammoniumchloride solution and brine, dried over sodium sulfate, and filtered.The filtrate is concentrated under reduced pressure to give4-tert-butyl-N-{6-2-(5-mercaptopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamideas pale yellow foam (529 mg).

(2) A mixture of the above product (200 mg), potassium carbonate (100mg), ethyl iodide (97 mg) and dimethylformamide (4 ml)is stirred at roomtemperature for two hours under argon atmosphere, and diluted with 10%hydrochloric acid. The mixture is extracted with ethyl actate, and theorganic layer is washed with water (twice), and brine, and dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue is purified by preparative thin layer chromatography (solvent;chlroform/ethyl actate=15:1) and recrystallized from ethylactate/n-hexane to give 4-tert-butyl-N-{6-2-(5-ethylthiopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(90 mg) as colorless crystalline powder.

M.p. 177°-178° C.

EXAMPLE 196

The corresponding starting compounds are treated in the same manner asin Example 195 to give 4-tert-butyl-N-{6-2-(5-isopropylthiopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide.

M.p. 161.5°-162.5° C.

EXAMPLE 197

A mixture of 4-tert-butyl-N-{6-2-(5-bromopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(1.00 g), zinc cyanide (784 mg), tetrakis(triphenylphosphine)palladium(250 mg) and 1,3-dimethyl-2-imidazolidinone (40 ml) is stirred at 80° C.for 6 hours under argon atmosphere. The mixture is cooled to roomtemperature, and diluted with saturated aqueous ammonium chloridesolution. The mixture is extracted with ethyl acetate, and the organiclayer is washed with water (twice) and brine, dried over sodium sulfate,and filtered. The filtrate is concentrated under reduced pressure, andthe residue is purified by silica gel column chromatography (solvent;chloroform/ethyl acetate=10:1) and recrystallized fromtetrahydrofuran/ethyl acetate to give 4-tert-butyl-N-{6-2-(5-cyanopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(590 mg) as colorless crystalline powder.

M.p. 196°-197° C.

EXAMPLE 198

A mixture of 4-tert-butyl-N-{6-2-(5-bromopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(1.00 g), trimethylsilylacetylene (330 mg),bis(triphenylphosphine)palladium (II) chloride (58 mg), copper (I)iodide (32 mg), triethylamine (420 mg) and dimethylformamide (5 ml) isstirred at 50° C. for three hours under argon atmosphere, and cooled toroom temperature. The mixture is diluted with saturated aqueous ammoniumchloride solution, and extracted with ethyl acetate. The organic layeris washed with water and brine, and dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue is purified bysilica gel column chromatography (solvent; chloroform/ethylacetate=40:1), and recrystallized from ethyl acetate/n-hexane to give4-tert-butyl-N-{6-2-(5-trimethylsilylethynylpyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(837 mg) as colorless crystalline powder.

M.p. 200°-202° C.

EXAMPLE 199

The corresponding starting compounds are treated in the same manner asin Example 198 to give 4-tert-butyl-N-{6-2-(5-(3-hydroxy-3-methyl-1-butynyl)pyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide.

M.p. 172.5°-173.5° C.

EXAMPLE 200

A mixture of 4-tert-butyl-N-{6-2-(5-trimethylsilylethynylpyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(667 mg), potassium carbonate (299 mg) and dry methanol (13 ml) isstirred at 0° C. for two hours, and diluted with saturated aqueousammonium chloride solution, and extracted with ethyl acetate. Theorganic layer is washed with water and brine, dried over sodium sulfate,and filtered. The filtrate is concentrated under reduced pressure, andthe residue is purified by silica gel column chromatography (solvent;chloroform/ethyl acetate=30:1) to give 4-tert-butyl-N-{6-2-(5-ethynylpyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}-benzenesulfonamide(502 mg) as colorless crystalline powder.

M.p. 207°-210° C.

EXAMPLE 201

A mixture of 4-tert-butyl-N-{6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!-5-(4-diethoxymethyllphenyl)pyrimidin-4-yl}benzenesulfonamide(558 mg), p-toluenesulfonic acid hydrate (50 mg), tetrahydrofuran (18ml) and water (6 ml) is stirred at room temperature for one hour. Themixtrue is evaporated to remove the solvent, and the residue is dilutedwith ethyl acetate. The ethyl acetate layer is washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (solvent; chloroform/ethyl acetate=2:1) andrecrystallized from chloroform/ethyl acetate to give 4-tert-butyl-N-{6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!-5-(4-formylphenyl)pyrimidin-4-yl}-benzenesulfonamide(345 mg) as colorless crystalline powder.

M.p. 223°-224° C.

EXAMPLE 202

A mixture of 4-tert-butyl-N-{6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!-5-(4-formylphenyl)pyrimidin-4-yl}benzenesulfonamide(269 mg), (carbethoxyethylidene)triphenylphosphorane (242 mg) andchloroform (5 ml) is stirred at room temperature for four hours, and themixture is diluted with chloroform, washed with 10% hydrochloric acid,water, and brine. The mixture is dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue is purified bysilica gel column chromatography (solvent; hexane/ethyl acetate=1:1),and recrystallized from ethyl acetate/n-hexane to give ethyl (E)-3-{4-4-(4-tert-butylphenylsulfonylamino)-6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!pyrimidin-5-yl!}phenylacrylate(261 mg) as colorless crystalline powder.

M.p. 172°-173° C.

EXAMPLE 203

A mixture of ethyl (E)-3-{4- 4-(4-tert-butylphenylsulfonylamino)-6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!pyrimidin-5-yl!}phenylacrylate(182 mg), 1N sodium hydroxide solution (0.56 ml), tetrahydrofuran (3 ml)and water (1 ml) is stirred at room temperature for 30 hours, anddiluted with chloroform. The mixture is acidified with 10% aqueoushydrochlorid acid solution. The mixture is extracted twice withchloroform, and the organic layer is washed with brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue is purified by preparative thin layer chromatography (solvent;chloroform/methanol=10:1), and crystallized from ethyl acetate/n-hexaneto give (E)-3-{4- 4-(4-tert-butylphenylsulfonylamino)-6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!pyrimidin-5-yl!}phenylacrylicacid (31 mg) as colorless crystalline powder.

M.p. 196°-204° C.

EXAMPLE 204

The corresponding starting compounds are treated in the same manner asin Example 203 to give 4- 4-(4-tert-butylbenzenesulfonamido)-6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!pyrimidin-5-yl!benzoic acid.

M.p. 226°-227° C.

EXAMPLES 205-206

To a stirred solution of 4-tert-butyl-N-{6-2-(5-bromopyrimidin-2-yloxy)ethoxy!-5-(2-methoxyphenylthio)pyrimidin-4-yl}benzenesulfonamide(464 mg) in chloroform (9 ml) is added 3-chloroperbenzoic acid (217 mg)at 0° C. and the mixture is stirred at 0° C. for two hours. The reactionmixture is diluted with saturated aqueous sodium hydrogen carbonatesolution and extracted three times with chloroform. The organic layer iswashed with brine, dried over sodium sulfate, and filtered. The filtrateis concentrated under reduced pressure. The residue is purified bypreparative thin layer chromatography (solvent; chloroform/ethylacetate=10:1). The eluated less polar fractions are combined andrecrystallized from methylene chloride/ethyl aceate to give4-tert-butyl-N-{6-2-(5-bromopyrimidin-2-yloxy)ethoxy!-5-(2-methoxyphenylsulfonyl)pyrimidin-4-yl}benzenesulfonamide(197 mg) as colorless crystalline powder.

M.p. 208°-210° C.

Separately, the more polar fractions are combined and crystallized fromethyl acetate/n-hexane to give 4-tert-butyl-N-{6-2-(5-bromopyrimidin-2-yloxy)ethoxy!-5-(2-methoxyphenylsulfinyl)pyrimidin-4-yl}benzenesulfonamide(167 mg) as colorless crystalline powder.

M.P. 163°-164.5° C.

EXAMPLE 207

To a suspension of sodium hydride (65 mg) in dimethylacetamide (0.5 ml)and tetrahydrofuran (0.5 ml) is added dropwise a solution of4-(2-hydroxy-1,1-dimethylethyl)-N-{6-2-hydroxyethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(135 mg) in dimethylacetamide (2 ml) and THF (2 ml) solution over periodof 5 minutes at room temperature, and thereto is added5-bromo-2-chloropyrimidine (399 mg). The mixture is stirred at roomtemperature for 6 days. The reaction mixture is acidified with colddiluted hydrochloric acid, and extracted with ethyl acetate. The organiclayer is washed with water and saturated brine, dried over anhydroussodium sulfate, and evaporated to remove the solvent. The oily residueis purified by silica gel column chromatography (solvent;chloroform/ethyl acetate=100:1), and evaporated to remove the solvent.The resulting crude crystals are recrystallized from methylenechloride/isopropyl ether to give 4-2-(5-bromopyrimidin-2-yloxy)-1,1-dimethylethyl!-N-{6-2-(5-bromopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(77 mg) as colorless crystals.

M.p. 156°-158° C.

EXAMPLE 208

To a solution of 4-tert-butyl-N-{6-2-(5-hydroxypyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(200 mg) in dimethylformamide (4 ml)is added potassium carbonate (154mg), 5-bromo-2-chloropyrimidine (216 mg), and the mixture is stirred at50° C. for two hours. The reaction mixture is acdified with coldhydrochloric acid, and extracted with ethyl acetate. The organic layeris washed with water and brine, and dried over anhydrous sodium sulfate,and evaporated to remove the solvent. The oily residue is purified bysilica gel column chromatography (solvent; chloroform/ethylacetate=50:1), and the fractions are evaporated to remove the solvent.The resulting crude crystals are recrystallized from methylenechloride/isopropyl ether to give 4-tert-butyl-N-{6-2-(5-(5-bromopyrimidin-2-yloxy)pyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(238 mg) as colorless needles.

M.p. 183°-184° C.

EXAMPLES 209-213

The corresponding starting compounds are treated in the same manner asin Example 208 to give the compounds as listed in Table 26.

                                      TABLE 26                                    __________________________________________________________________________     ##STR262##                                                                   Ex. No.                                                                           R.sup.1             Physical Properties                                   __________________________________________________________________________    209                                                                                ##STR263##         M.p. 191-192° C.                               210                                                                                ##STR264##         M.p. 119-120° C.                               211                                                                                ##STR265##         M.p. 137-138° C.                               212                                                                                ##STR266##         M.p. 166-168° C.                               213 CONHCH.sub.3        M.p. 84-88° C.                                 __________________________________________________________________________

EXAMPLE 214

A mixture of 4-tert-butyl-N-{6-2-(5-(α-styryl)pyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(130 mg), 10% palladium-carbon (42 mg), ethanol (1 ml) andtetrahydrofuran (10 ml) is stirred at room temperature under hydrogenatmosphere for one hour. The catalyst is removed by filtration, and thefiltrate is concentrated under reduced pressure. The residue is purifiedby preparative tin layer chromatography (solvent; chloroform/ethylacetate=15:1), and crystallized from ethyl aetate/diisopropyl ether togive 4-tert-butyl-N-{6-2-(5-(α-phenethyl)pydmidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide(111 mg) as colorless needles.

M.p. 158.5°-160.5° C.

Reference Example 1

To 1,3-propanediol (7 ml) is added sodium hydride (60% dispersion-type,312 mg), and thereto is added4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide(707 mg). The reaction mixture is reacted at 90° C. for two hours, andthen reacted at 130° C. for one hour. The reaction solution is acidifiedwith 10% hydrochloric acid, and extracted with ethyl acetate, and theethyl acetate layer is washed, dried, and concentrated to dryness underreduced pressure. The residue is purified by silica gel columnchromatography (solvent; chloroform/ethyl acetate=10:1), andcrystallized from ethyl acetate/diisopropyl ether to give4-tert-butyl-N-{6-(3-hydroxypropyloxy)-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide(315 mg) as crystals.

M.p. 113°-114° C.

Reference Examples 2-12

The corresponding starting compounds are treated in the same manner asin Reference Example 1 to give the compounds as listed in Tables 27-28.

                  TABLE 27                                                        ______________________________________                                         ##STR267##                                                                   Ref.                                Physical                                  Ex. No.                                                                             Ring A             R.sup.1    Properties                                ______________________________________                                               ##STR268##        H          M.P. 182- 185° C.                  3                                                                                    ##STR269##        H          M.P. 189- 191° C.                  4                                                                                    ##STR270##        H          M.P. 188- 190° C.                  5                                                                                    ##STR271##                                                                                       ##STR272##                                                                              M.P. 247° C. (decom.)              6                                                                                    ##STR273##        (CH.sub.2).sub.2 CH.sub.3                                                                M.P. 121- 122° C.                  7                                                                                    ##STR274##                                                                                       ##STR275##                                                                              M.P. 211- 216° C.                  ______________________________________                                    

                  TABLE 28                                                        ______________________________________                                         ##STR276##                                                                                                         Physical                                Ref. Ex. No.                                                                          Ring B       Q        R.sup.1 Properties                              ______________________________________                                                 ##STR277##  CH.sub.2                                                                                ##STR278##                                                                           M.p. 109- 110° C.                9                                                                                      ##STR279##  O                                                                                       ##STR280##                                                                           M.p. 124- 126.5° C.              10                                                                                     ##STR281##  O                                                                                       ##STR282##                                                                           MS (m/z): 572 (MH.sup.+)                11                                                                                     ##STR283##  S                                                                                       ##STR284##                                                                           M.p. 107- 108° C.                12                                                                                     ##STR285##  S        H       M.p. 165- 166.5° C.              ______________________________________                                    

Reference Example 13

(1) To a stirred mixture of tetrahydrofuran (400 ml) and ethylene glycol(60 ml) is added sodium hydride (60% dispersion-type, 3.38 g) underice-cooling, and thereto is added4,6-dichloro-5-(4-methyllphenyl)pyrimidine (20.0 g). The mixture isstirred under ice-cooling for 30 minutes, and stirred at roomtemperature for two hours. The mixture is made weak acidic with aceticacid, and concentrated under reduced pressure. The residue is dissolvedin ethyl acetate, washed, dried, and concentrated to dryness underreduced pressure. The residue is crystallized from hexane to give2-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (21.85 g).

M.p. 62°-64° C.

(2) A mixture of2-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yloxy}-ethanol (21.85 g),sodium azide (10.7 g) and dimethyformamide (260 ml) is heated withstirring at 75°-80° C. overnight. After cooling, the mixture is treatedwith water, and extracted with ethyl acetate. The ethyl acetate layer iswashed, dried, and evaporated to remove the solvent. The residue iscrystallized from hexane to give2-{6-azido-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (19.6 g).

M.p. 83.5°-85° C.

MS (m/z): 271 (M⁺)

(3) A mixture of 2-{6-azido-5-(4-methylphenyl)pyrimidin-4-yloxy}-ethanol(19.6 g), 10% palladium-carbon (50% moist) (4.0 g) and ethanol (240 ml)is subjected to catalytic hydrogenation at room temperature underhydrogen atmosphere (1 atm) for one hour. The catalyst is removed byfiltration, and the filtrate is concentrated under reduced pressure. Theresidue is recrystallized from ethyl acetate/n-hexane to give2-{6-amino-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (15.9 g).

M.p. 104°-105° C.

Reference Example 14

(1) To a solution of 4,6-dichloro-5-(4-methylphenyl)pyrimidine (4.14 g)in ether (20 ml) is added 27% ammonia-ethanol solution (30 ml), and thereaction mixture is reacted at room temperature in a sealed tube forthree days. The mixture is concentrated under reduced pressure, and theresidue is purified by silica gel column chromatography (solvent;hexane/ethyl acetate=(10:1)˜ethyl acetate) to give6-chloro-5-(4-methylphenyl)pyrimidin-4-amine (1.89 g).

M.p. 168°-171° C.

(2) A mixture of 6-chloro-5-(4-methylphenyl)pyrimidin-4-amine (500 mg),ethylene glycol (10 ml) and sodium hydride (60% dispersion-type, 0.46 g)is reacted at 70° C. for two hours, and reacted at 90° C. for fivehours. The mixture is treated with saturated aqueous ammonium chloridesolution, and extracted with ethyl acetate. The ethyl acetate layer iswashed, dried, and evaporated to remove the solvent. The residue iscrystallized from hexane/ethyl acetate to give2-{6-amino-5-(4-methylphenyl)pyrimidin-4-yloxy}-ethanol (422 mg).

M.p. 91.5°-93.5° C.

Reference Example 15

To a solution of 2-{6-amino-5-(4-methylphenyl)pyrimidin-4-yloxy}-ethanol(7.54 g) in tetrahydrofuran (150 ml) is added sodium hydride (60%dispersion-type, 1.47 g), and thereto is added5-bromo-2-chloropyrimidine (7.73 g), and the mixture is stirred at roomtemperature overnight. To the reaction solution is added saturatedaqueous ammonium chloride solution, and the mixture is evaporated toremove the solvent. The precipitated crystals are collected byfiltration, washed and dried. The crude crystals are purified by silicagel column chromatography (solvent; chloroform/methanol=100:1˜80:1), andrecrystallized from tetrahydrofuran/diethyl ether to give 6-2-(5-bromopyrimidin-2-yloxy)ethoxy!-5-(4-methylphenyl)pyrimidin-4-amine(11.27 g).

M.p. 178.5°-179.5° C.

IR (nujol, cm-1): 3400, 3300, 3130, 1640, 1580

MS (m/z): 401,403 (M⁺)

Reference Example 16

(1) To a solution of 4,6-dichloropyrimidine (1.33 g) and4-tert-butylbenzenesulfonamide (1.96 g) in dimethylformamide (20 ml) isadded sodium hydride (60% dispersion-type, 714 mg). The mixture isstirred at room temperature for two hours, and the reaction solution isdiluted with 10% hydrochloric acid and water. The mixture is extractedwith ethyl acetate, and the ethyl acetate layer is washed, dried, andevaporated to remove the solvent. The residue is recrystallized fromethyl acetate to give4-tert-butyl-N-(6-chloropyrimidin-4-yl)benzenesulfonamide (2.02 g).

M.p. 225°-226.5° C.

IR (nujol, cm-1): 3035, 1630, 1595, 1575

MS (m/z): 325 (M⁺)

(2) To ethylene glycol (20 ml) is added sodium hydride (60%dispersion-type, 1.03 g), and thereto is added4-tert-butyl-N-(6-chloropyrimidin-4-yl)benzenesulfonamide (1.66 g). Themixture is stirred at 60° C. for 20 hours. After cooling, the mixture isacidified with 10% hydrochloric acid, and extracted with ethyl acetate.The ethyl acetate layer is washed, dried, and evaporated to remove thesolvent. The residue is crystallized from ethyl acetate to give4-tert-butyl-N-{6-(2-hydroxyethoxy)pyrimidin-4-yl}benzenesulfonamide(1.58 g).

M.p. 169°-170.5° C.

IR (nujol, cm-1): 3440, 1600, 1570

FABMS (m/z): 352 (M⁺)

(3) To a solution of 4-tert-butyl-N-6-(2-hydroxyethoxy)pyrimidin-4-yl)benzenesulfonamide (210 mg) indimethylformamide (4 ml) is added N-bromosuccinimide (116 mg), and themixture is stirred at room temperature for one hour. The mixture istreated with aqueous sodium hydrogen sulfite solution, and extractedwith ethyl acetate. The ethyl acetate layer is washed, dried andevaporated to remove the solvent. The residue is purified by silica gelcolumn chromatography (solvent; chloroform/methanol=40:1), andrecrystallized from hexane/ethyl acetate to give N-5-bromo-6-(2-hydroxyethoxy)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(169 mg).

M.p. 146°-147.5° C.

IR (nujol, cm-1): 3360, 3200, 1620, 1575

FABMS (m/z): 432,430 (MH⁺)

(4) To a solution of N-5-bromo-6-(2-hydroxyethoxy)pyrimidin-4-yl!-4-tert-butylbenzenesulfonamide(3.10 g) in dimethylacetamide (30 ml) is added sodium hydride (60%dispersion-type, 720 mg), and the mixture is stirred at room temperaturefor 30 minutes. To the mixture is added 2-chloro-5-methylthiopyrimidine(1.51 g), and the mixture is stirred at room temperature overnight. Thereaction solution is treated with 10% hydrochloric acid and saturatedammonium chloride solution, and extracted with ethyl acetate. The ethylacetate layer is washed, dried, and evaporated to remove the solvent.The residue is purified by silica gel column chromatography (solvent;chloroform/ethyl acetate=10:1), and recrystallized from hexane/ethylacetate to give N-{5-bromo-6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(3.34 g).

M.p. 120°-121° C.

IR (nujol, cm-1): 1585, 1575, 1550

FABMS (m/z): 556,554 (MH⁺)

Reference Example 17

(1) To a mixture of 4,6-dichloropyrimidine (5.0 g), ethylene glycol (100ml) and tetrahydrofuran (100 ml)is added sodium hydride (60%dispersion-type, 1.34 g) under ice-cooling. The mixture is stirred atthe same temperature for two hours, and evaporated to remove thesolvent. The residue is extracted with ethyl acetate, and the ethylacetate extract is dried, and concentrated under reduced pressure. Theresidue is purified by silica gel column chromatography (solvent;chloroform/ethyl acetate=5:1˜2:1) to give2-(6-chloropyrimidin-4-yloxy)ethanol (5.67 g) as an oily product.

IR (nujol, cm-1): 3300, 1575, 1545

FABMS (m/z): 175 (MH⁺)

(2) To a solution of 2-(6-chloropyrimidin-4-yloxy)ethanol (5.61 g) indimethylformamide (60 ml) is added sodium azide (4.18 g), and themixture is stirred at 70° C. for 20 hours. After cooling, the reactionsolution is treated with water, and extracted with ethyl acetate. Theethyl acetate layer is dried, and evaporated to remove the solvent. Theresidue is purified by silica gel column chromatography (solvent;hexane/ethyl acetate=1:1) to give 2-(6-azidopyrimidin-4-yloxy)ethanol(1.68 g).

M.p. 49°-50° C.

IR (nujol, cm-1): 3280, 2070, 1600, 1550

FABMS (m/z):181 (MH⁺)

(3) A mixture of 2-(6-azidopyrimidin-4-yloxy)ethanol (1.64 g), 10%palladium-carbon (0.25 g) and ethanol (20 ml) is subjected to catalytichydrogenation at room temperature for one hour under hydrogen atmosphere(1 atm). The catalyst is removed by filtration, and the filtrate isconcentrated. The residue is recrystallized from ethanol/diethyl etherto give 2-(6-aminopyrimidin-4-yloxy)ethanol (1.11 g).

M.p. 133°-137° C.

IR (nujol, cm-1): 3360, 3200, 1660, 1610, 1550

FABMS (m/z): 156 (MH⁺)

(4) To a suspension of 2-(6-aminopyrimidin-4-yloxy)ethanol (400 mg) inmethanol (4 ml) is added dropwise a solution of bromine (437 mg) inmethanol (2 ml). The mixture is evaporated to remove the solvent, andthe residue is dissolved in ethyl acetate. The mixture is treated withsaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate/tetrahydrofuran. The organic layer is washed, dried, andevaporated to remove the solvent to give2-(6-amino-5-bromopyrimidin-4-yloxy)ethanol (632 mg).

IR (nujol, cm-1): 3480, 3420, 3390, 3290, 1640, 1580

MS (m/z): 235,233 (M⁺)

(5) To a solution of 2-(6-amino-5-bromopyrimidin-4-yloxy)ethanol (611mg) in dimethylformamide (20 ml) is added sodium hydride (60%dispersion-type, 125 mg), and the mixture is stirred for 20 minutes. Tothe mixture is added 2-chloro-5-methylthiopyrimidine (461 mg), and themixture is stirred at room temperature for three hours. To the mixtureis added ice-water, and the mixture is extracted with ethyl acetate. Theethyl acetate layer is washed, dried, and evaporated to remove thesolvent. The residue is purified by silica get column chromatography(solvent; chloroform/methanol=20:1), and crystallized from ethylacetate/diisopropyl ether to give 5-bromo-6-2-(5-methythiopyrimidin-2-yloxy)ethoxy!pyrimidine-4-amine (501 mg).

M.p. 126°-129° C.

IR (nujol, cm-1): 3450, 3270, 1635, 1585, 1570, 1540

MS (m/z): 359, 357 (M⁺)

(6) To a solution of 5-bromo-6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!pyrimidine-4-amine (102 mg) intetrahydrofuran (2 ml) is added sodium hydride (60% dispersion-type, 34mg), and thereto is added 4-tert-butylbenzenesulfonyl chloride (198 mg).The mixture is stirred at room temperature for 20 minutes, and theretoare added a drop of pyridine and water. The mixture is stirred at roomtemperature for 30 minutes, and neutralized with saturated aqueousammonium chloride solution. The mixture is extracted with ethyl acetate,and the ethyl acetate layer is washed, dried, and evaporated to removethe solvent. The residue is purified by preparative thin layerchromatography (solvent; chloroform/methanol=15:1), and recrystallizedfrom hexane/ethyl acetate to give N-{5-bromo-6-2-(5-methylthiopyrimidin-2-yloxy)ethoxy!-pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide(135 mg). The physical properties thereof are the same as those of thecompound obtained in Reference Example 16-(4).

Reference Example 18

(1) To a solution of diethyl(4-methylphenyl)malonate (9.45 g) andbutyramidine hydrochloride (5.00 g) in methanol (25 ml) is added 28%sodium methoxide (19.67 g) under ice-cooling, and the mixture is stirredat room temperature overnight. After the reaction is complete, thereaction solution is concentrated to the half volume thereof, and theresultant is diluted with water. The mixture is acidified with 10%hydrochloric acid, and the precipitated crystals are collected byfiltration, washed, and dried to give5-(4-methylphenyl)-4,6-dihydroxy-2-n-propylpyrimidine (5.17 g) ascrystalline powder.

M.p. >300° C.

(2) A mixture of the above product (5.14 g), diethylphenylamine (5 ml)and phosphorus oxychloride (20 ml) is refluxed for two hours. After thereaction is complete, the mixture is evaporated to remove phosphorusoxychloride, and poured gradually into water (300 ml). The mixture isstirred at room temperature for 20 minutes, and extracted with ether.The extract is washed, dried, treated with activated carbon, andevaporated to remove the solvent to give5-(4-methylphenyl)-4,6-dichloro-2-n-propylpyrimidine (5.91 g) ascrystals.

M.p. 91°-93° C.

(3) To a suspension of the above product (2.10 g) in dimethylsulfoxide(25 ml) are added 4-tert-butylbenzenesulfonamide (1.91 g) and potassiumcarbonate (4.13 g), and the mixture is stirred at 80° C. for 9 hours.After cooling, the reaction mixture is added into cold hydrochlorideacid, and the mixture is extracted with ethyl acetate. The extract iswashed, dried, and evaporated to remove the solvent. The residue ispurified by silica gel column chromatography (solvent; chloroform/ethylacetate=50:1), and crystallized from n-hexane to give 4-tert-butyl-N-6-chloro-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl!benzenesulfonamide(3.0 g) as powder.

M.p. 138°-139° C.

(4) To a solution of the above product (2.94 g) in ethylene glycol (50ml) is added sodium (0.74 g) in portions at room temperature, and themixture is stirred at 135° C. for 18 hours. After cooling, the reactionmixture is diluted with diluted hydrochloric acid under cooling, andextracted with ethyl acetate. The extract is washed, dried, andevaporated to remove the solvent. The residue is purified by silica gelcolumn chromatography (solvent; chloroform/ethyl acetate=50:1) to give4-tert-butyl-N-6-(2-hydroxyethoxy)-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl!benzensulfonamide(2.21 g) as crystalline powder.

M.p. 133°-134° C.

Reference Example 19

Diethyl(4-methylphenyl)malonate and isobutyramidine hydrochloride aretreated in the same manner as in Reference Example 18 to give4-tert-butyl-N-6-(2-hydroxyethoxy)-5-(4-methylphenyl)-2-isopropylpyrimidin-4-yl!benzensulfonamide.

M.p. 143°-144° C.

Reference Example 20

(1) To a solution of thiophene (1.69 g) in anhydrous tetrahydrofuran (20ml) is added dropwise a 1.6M n-butyl lithium/n-hexane solution (11.4 ml)at 0° C. under argon atmosphere over a period of 30 minutes. To themixture is added dropwise and gradually a solution of5-(4-methylphenyl)-4,6-dichloropyrimidine (4.0 g) in anhydroustetrahydrofuran (5 ml) at -60° C. The mixture is warmed to 0° C., andstirred for 1.5 hour. After the reaction is complete, to the mixture areadded acetic acid (1.5 g) and water (0.25 g), and further added theretoa solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.70 g) intetrahydrofuran (5 ml), and the mixture is stirred at 0° C. for onehour. The mixture is treated with an active charcoal, and extracted witha mixture of ethyl acetate and aqueous citric acid solution. The extractis washed, dried and evaporated to remove the solvent. The residue ispurified by silica gel column chromatography (solvent; n-hexane/ethylacetate=50:1) to give5-(4-methylphenyl)-4,6-dichloro-2-(2-thienyl)pyrimidine (2.64 g) aspowder.

M.p. 119.5°-120° C.

(2) The above product (2.64 g) is treated in the same manner as inReference Example 18-(3) to give 4-tert-butyl-N-6-chloro-5-(4-methylphenyl)-2-(2-thienyl)pyrimidin-4-yl!benzenesulfonamide(3.38 g) as powder.

M.p. >300° C.

(3) The above product (3.38 g) is treated in the same manner as inReference Example 18-(4) to give 4-tert-butyl-N-6-(2-hydroxyethoxy)-5-(4-methylphenyl)-2-(2-thienyl)pyrimidin-4-yl!benzenesulfonamide(2.11 g) as powder.

M.p. >300° C.

Reference Example 21

(1) A solution of 5-(4-methylphenyl)-4,6-dichloropyrimidine in ether iscooled at -30° C., and thereto is added dropwise a 1.8M phenyllithium/cyclohexane solution. The reaction mixture is treated in thesame manner as in Reference Example 20-(1) to give5-(4-methylphenyl)-4,6-dichloro-2-phenylpyrimidine as crystallinepowder.

M.p. 165°-166.5° C.

(2) The above product is treated in the same manner as in ReferenceExample 18-(3) to give 4-tert-butyl-N-6-chloro-5-(4-methylphenyl)-2-phenylpyrimidin-4-yl!benzenesulfonamide aspowder.

M.p. 249°-250° C.

(3) The above product is treated in the same manner in Reference Example18-(4) to give 4-tert-butyl-N-6-(2-hydroxyethoxy)-5-(4-methylphenyl)-2-phenylpyrimidin-4-yl!benzenesulfonamideas crystals.

M.p. 197.5°-198.5° C.

Reference Example 22

2-Chloro-5-bromopyrimidine and 2-furyltributyltin are treated in thesame manner as in Example 190 to give 2-chloro-5-(2-furyl)pyrimidine.

M.p. 134.5°-136° C.

Reference Example 23

2-Chloro-5-bromopyrimidine and 2-thienyltributyltin are treated in thesame manner as in Example 190 to give 2-chloro-5-(2-thienyl)pyridine.

M.p. 124.5°-125.5° C.

Reference Example 24

2-Chloro-5-bromopyrimidine and 3-thienyltributyltin are treated in thesame manner as in Example 190 to give 2-chloro-5-(3-thienyl)pyrimidine.

M.p. 154°-157° C.

Reference Example 25

To a solution of 2-chloro-5-methoxypyrimidine (1.90 g) which ispreviously prepared by a method disclosed in J. Chem, Soc., 4590 (1960)in methylene chloride (30 ml) is added dropwise boron tribromide (4.97ml) over a period of 15 minutes in a dry ice/acetone bath. The mixtureis stirred at room temperature for 22 hours, and thereto is addeddropwise methanol (30 ml) in a dry ice/acetone bath. The reactionmixture is concentrated under reduced pressure, and the pH value thereofis adjusted to pH 5 with aqueous sodium hydroxide solution. The mitureis extracted twice with ethyl acetate, and the extract is washed withwater and brine, dried over anhydrous sodium sulfate, and evaporated toremove the solvent. The resulting crystals are washed with n-hexane togive 2-chloro-5-hydroxypyrimidine (1.47 g) as colorless crystals.

M.p. 194°-195° C.

Reference Example 26

(1) A solution of 3-hydroxymethylthiophene and thionyl chloride inmethylene chloride is stirred under ice-cooling for 30 minutes. To thereaction mixture is added water, and the mixture is extracted withchloroform. The organic layer is washed with water, saturated aqueoussodium hydrogen carbonate solution and saturated brine, and dried. Theresidue is concentrated under reduced pressure to give3-chloromethylthiophene (1.61 g).

(2) A mixture of 2-chloro-5-hydroxypyrimidine (200 mg),3-chloromethylthiophene (610 mg), potassium carbonate (635 mg) anddimethylformamide (3 ml) is stirred at 50° C. for one hour. After thereaction is complete, to the reaction mixture is added water, andextracted with ethyl acetate. The organic layer is washed with water andsaturated brine, dried, and concentrated under reduced pressure. Theresidue is purified by silica gel column chromatography (solvent;n-hexane/ethyl acetate=20:1→20:3), and evaporated to remove the solventto give 2-chloro-5-(3-thienylmethoxy)pyrimidine (345 mg) as colorlessneedles.

M.p. 73°-76° C.

Reference Examples 27-32

The corresponding starting compounds are treated in the same manner asin Reference Example 26 to give the compounds as listed in Table 29.

                  TABLE 29                                                        ______________________________________                                        Ref.                         Physical                                         Ex. No.                                                                             Structure              Properties                                       ______________________________________                                        27                                                                                   ##STR286##            Oil                                              28                                                                                   ##STR287##            M.p. 100-103° C.                          29                                                                                   ##STR288##            M.p. 50-52° C.                            30                                                                                   ##STR289##            M.p. 65-67° C.                            31                                                                                   ##STR290##            M.p. 64-67° C.                            32                                                                                   ##STR291##            M.p. 103-105° C.                          ______________________________________                                    

EFFECTS OF THE INVENTION

The desired compounds I! of the present invention and a pharmaceuticallyacceptable salt thereof show an excellent endothelin antagonisticactivity so that they are useful in the prophylaxis or treatment ofdisorders associated with endothelin activities such as hypertension,pulmonary hypertension, renal hypertension, Raynaud disease, bronchialasthma, gastric ulcer, inflammatory bowl disease (Crohn's disease),shock, carcinogenesis, restenosis after angioplasty, organ dysfunctionafter transplantation, diabetes, thrombosis, arteriosclerosis, heartfailure, acute renal insufficiency, glomerulonephritis,cyclosporin-induced nephrotoxicity, myocardial infarction, anginapectoris, arrhythmia, glaucoma, migraine, cerebrovascular spasm andcerebral infarction, and the like. Besides, the present compounds I! anda pharmaceutically acceptable salt thereof are low toxic and hence, theyshow high safety as a medicament.

What is claimed is:
 1. A benzenesulfonamide derivative of the formulaI!: ##STR292## wherein Ring A and Ring B are the same or different andeach a substituted or unsubstituted benzene ring,Q is a single bond or agroup of the formula: --O--, --S--, --SO--, --SO₂ -- or --CH₂ --, Y is agroup of the formula: --O--, --S-- or --NH--, Alk is a lower alkylenegroup or a lower alkenylene group, Z is a single bond or a group of theformula: --O-- or --NH--, R is a substituted or unsubstituted aromaticheterocyclic or aryl group, R¹ is hydrogen atom, trifluoromethyl group,a substituted or unsubstituted lower alkyl group, a substituted orunsubstituted lower alkenyl group, a mono- or di-lower alkylamino group,a substituted or unsubstituted lower alkylthio group, a substituted orunsubstituted lower alkoxy group, a substituted or unsubstituted loweralkynyl group, an aromatic heterocyclic group, a substituted orunsubstituted aliphatic heterocyclic group or an aryl group, providedthat when Z is a single bond, R is a substituted or unsubstitutedaromatic heterocyclic group,or a pharmaceutically acceptable saltthereof.
 2. The compound according to claim 1, wherein Ring A and Ring Bare the same or different and each a benzene ring having optionally 1 to3 substituents selected from a halogen atom; a lower alkyl group; alower alkoxy group; a lower alkenyl group; a lower alkynyl group; acycloalkyl group; a lower alkylthio group; trifluoromethyl group;carboxyl group; cyano group; tetrazolyl group; formyl group; carbamoylgroup; a mono- or di-lower alkylaminocarbonyl group; a loweralkoxycarbonyl group; a lower alkoxycarbonyl-lower alkoxy group; a loweralkoxycarbonyl-lower alkyl group; a lower alkoxycarbonyl-lower alkenylgroup; a di-lower alkoxy-substituted lower alkyl group; ahydroxy-substituted lower alkyl group; a carboxyl-substituted loweralkyl group; a carboxyl-substituted lower alkenyl group; acarboxyl-substituted lower alkoxy group; a bromopyrimidinyloxy-loweralkyl group; a lower alkylenedioxy group; an aryl-lower alkoxy group andan arylaminocarbonyl group,R is an aromatic heterocyclic or aryl groupwhich may optionally have 1 to 4 substituents selected from a halogenatom; a protected or unprotected hydroxy group; nitro group; cyanogroup; amino group; formyl group; carboxyl group; carbamoyl group; anN-lower alkylcarbamoyloxy group, an N-hydroxy-iminomethyl group; anN-lower alkoxyiminomethyl group; a lower alkyl group; ahydroxy-substituted lower alkyl group; a cycloalkyl group; a loweralkoxy-lower alkyl group; a lower alkoxycarbonyl-lower alkenyl group;trifluoromethyl group; a hydroxy- and aryl-substituted lower alkylgroup; a lower alkylthio group; a mono- or di-lower alkylamino group; alower alkanoylamino group; a lower alkoxy group; a lower alkoxy groupsubstituted by a protected or unprotected carboxyl group; an aryloxygroup; a lower alkoxycarbonyl group; a lower alkoxy-lower alkenyl group;a lower alkanoyl group; an arylcarbonyl group; a lower alkenyloxy group;a hydroxy-substituted lower alkynyl group; a lower alkynyl group beingoptionally protected by a trimethylsilyl group; a cyano-lower alkoxygroup; a cycloalkyl-lower alkoxy group; a lower alkylsulfinyl group; alower alkylsulfonyl group; an aryl group; a phenyl-lower alkyl group; anaromatic heterocyclic group-substituted lower alkyl group; an aromaticheterocyclic group-substituted lower alkoxy group; a phenyl-loweralkenyl group; a phenyl-lower alkoxy group; an arylcarbonylamino group;an aromatic heterocyclic group-substituted oxy group having optionally 1to 3 substituents selected from a halogen atom and a lower alkyl group;and an aromatic heterocyclic group having optionally a lower alkylsubstituent, R¹ is (1) hydrogen atom, (2) trifluoromethyl group, (3) alower alkyl group having optionally 1 to 3 substituents selected from ahalogen atom, carboxyl group, a lower alkoxycarbonyl group, an aromaticheterocyclic group and an aryl group, (4) a lower alkenyl group, (5) amono- or di-lower alkylamino group, (6) a lower alkylthio group, (7) alower alkoxy group having optionally a hydroxy substituent or ahydroxy-lower alkoxy substitutent, (8) a lower alkynyl group havingoptionally a carboxyl substituent, (9) an aromatic heterocyclic group,(10) an aliphatic heterocyclic group having optionally a lower alkylsubstituent, or (11) an aryl group.
 3. The compound according to claim2, wherein the aromatic heterocyclic group is an aromaticheteromonocyclic or heterobicyclic group having 1 to 4 heteroatomsselected from nitrogen atom, oxygen atom and sulfur atom.
 4. Thecompound according to claim 2, wherein the aromatic heterocyclic groupis pyrrolyl group, imidazolyl group, furyl group, thienyl group,thiazolyl group, isooxazolyl group, oxazolyl group, oxazolinyl group,pyrazolyl group, quinazolinyl group, thienopyrimidinyl group, pyridylgroup, pyrimidinyl group, pyridazinyl group, pyrazinyl group, triazinylgroup, tetrazolyl group, quinolyl group, isoquinolyl group, quinoxalinylgroup, benzothiazolyl group, benzoxazolyl group, or benzimidazolylgroup, and the aliphatic heterocyclic group is piperazinyl group,pyrrolidinyl group, piperidyl group, homopiperidyl group,thiomorpholinyl group, or morpholinyl group, and the aryl group and thearyl moiety of the arylcarbonylamino group are phenyl group, a loweralkoxyphenyl group or naphthyl group.
 5. A pharmaceutical compositionwhich comprises a therapeutically effective amount of the compound asset forth in claim 1 in admixture with a conventional pharmaceuticallyacceptable carrier or diluent.
 6. A method for the treatment ofdisorders associated with endothelin activities, which comprisesadministering to a warm-blooded animal a therapeutically effectiveamount of the compound as set forth in claim 1.